0A4F4F9BD490A749D5437F821CF06DF1
ICH E6(R2): Good Clinical Practice- Integrated Addendum to E6(R1)
https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf
http://leaux.net/URLS/ConvertAPI Text Files/5AE3F5A7BC988661656811B9F800456A.en.txt
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This file was generated: 2020-07-14 04:57:57
| Indicators in focus are typically shown highlighted in yellow; |
Peer Indicators (that share the same Vulnerability association) are shown highlighted in pink; |
"Outside" Indicators (those that do NOT share the same Vulnerability association) are shown highlighted in green; |
Trigger Words/Phrases are shown highlighted in gray. |
Link to Orphaned Trigger Words (Appendix (Indicator List, Indicator Peers, Trigger Words, Type/Vulnerability/Indicator Overlay)
Applicable Type / Vulnerability / Indicator Overlay for this Input
Political / nomad
Searching for indicator nomads:
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p.000007: An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g.,
p.000007: Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics
p.000007: for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for
p.000007: Expedited Reporting).
p.000007:
p.000007: 1.61 Vulnerable Subjects
p.000007: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether
p.000007: justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a
p.000007: hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure,
p.000007: such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees
p.000007: of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable
p.000007: subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons,
p.000007: patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and
p.000007: those incapable of giving consent.
p.000007: 1.62 Well-being (of the trial subjects)
p.000007: The physical and mental integrity of the subjects participating in a clinical trial.
p.000007: ADDENDUM
p.000007: 1.63 Certified Copy
p.000007: A copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated
p.000007: signature or by generation through a validated process) to have the same information, including data that describe the
p.000007: context, content, and structure, as the original.
p.000007: 1.64 Monitoring Plan
p.000007: A document that describes the strategy, methods, responsibilities, and requirements for monitoring
p.000007: the trial.
p.000007: 1.65 Validation of Computerized Systems
p.000007: A process of establishing and documenting that the specified requirements of a computerized system can be
p.000007: consistently fulfilled from design until decommissioning of the system or transition to a new system. The
p.000007: approach to validation should be based on a risk assessment that takes into consideration the intended use of the
p.000007: system and the potential of the system to affect human subject protection and reliability of trial results.
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000008: 8
p.000008:
p.000008: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000008:
p.000008:
p.000008: 2. THE PRINCIPLES OF ICH GCP
p.000008:
...
Political / political affiliation
Searching for indicator party:
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p.000010: Current E6(R2) Addendum Step 4 version
p.000010: Code History
p.000010: Date
p.000010:
p.000010: E6(R2)
p.000010: Adoption by the Regulatory Members of the ICH Assembly under Step 4.
p.000010: Integrated Addendum to ICH E6(R1) document. Changes are integrated directly into the following sections of
p.000010: the parental Guideline: Introduction, 1.63, 1.64, 1.65, 2.10, 2.13, 4.2.5, 4.2.6,
p.000010: 4.9.0, 5.0, 5.0.1, 5.0.2, 5.0.3, 5.0.4, 5.0.5, 5.0.6, 5.0.7, 5.2.2,
p.000010: 5.5.3 (a), 5.5.3 (b), 5.5.3 (h), 5.18.3, 5.18.6 (e), 5.18.7, 5.20.1,
p.000010: 8.1
p.000010: 9 November
p.002016: 2016
p.002016:
p.002016:
p.002016: Legal notice: This document is protected by copyright and may be used, reproduced, incorporated into
p.002016: other works, adapted, modified, translated or distributed under a public license provided that ICH's
p.002016: copyright in the document is acknowledged at all times. In case of any adaption, modification or translation of the
p.002016: document, reasonable steps must be taken to clearly label, demarcate or otherwise identify that changes were
p.002016: made to or based on the original document. Any impression that the adaption, modification or translation of the
p.002016: original document is endorsed or sponsored by the ICH must be avoided.
p.002016: The document is provided "as is" without warranty of any kind. In no event shall the ICH or the
p.002016: authors of the original document be liable for any claim, damages or other liability arising from the use of the
p.002016: document.
p.002016: The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for documents where the
p.002016: copyright vests in a third party, permission for reproduction must be obtained from this copyright holder.
p.002016:
p.002016: ICH HARMONISED GUIDELINE
p.002016: INTEGRATED ADDENDUM TO ICH E6(R1): GUIDELINE FOR GOOD CLINICAL PRACTICE ICH
p.002016: E6(R2)
p.002016: ICH Consensus Guideline
p.002016:
p.002016: TABLE OF CONTENTS
p.002016: INTRODUCTION
p.000001: 1
p.000001: 1. GLOSSARY
p.000002: 2
p.000002: 2. THE PRINCIPLES OF ICH GCP
p.000009: 9
p.000009: 3. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)
p.000010: 10
p.000010: 3.1 Responsibilities
p.000010: 10
p.000010: 3.2 Composition, Functions and Operations
p.000011: 11
p.000011: 3.3 Procedures
p.000011: 11
p.000011: 3.4 Records
p.000012: 12
p.000012: 4. INVESTIGATOR
p.000013: 13
p.000013: 4.1 Investigator's Qualifications and Agreements
p.000013: 13
p.000013: 4.2 Adequate Resources
p.000013: 13
p.000013: 4.3 Medical Care of Trial Subjects
p.000014: 14
p.000014: 4.4 Communication with IRB/IEC
p.000014: 14
p.000014: 4.5 Compliance with Protocol
p.000014: 14
p.000014: 4.6 Investigational Product(s)
p.000015: 15
p.000015: 4.7 Randomization Procedures and Unblinding
p.000015: 15
p.000015: 4.8 Informed Consent of Trial Subjects
p.000016: 16
p.000016: 4.9 Records and Reports
p.000019: 19
p.000019: 4.10 Progress Reports
p.000019: 19
p.000019: 4.11 Safety Reporting
p.000020: 20
p.000020: 4.12 Premature Termination or Suspension of a Trial
p.000020: 20
p.000020: 4.13 Final Report(s) by Investigator
p.000020: 20
p.000020: 5. SPONSOR
p.000021: 21
p.000021: 5.0 Quality Management
p.000021: 21
p.000021: 5.1 Quality Assurance and Quality Control
p.000022: 22
p.000022: 5.2 Contract Research Organization (CRO)
...
p.000002: 1.15 Compliance (in relation to trials)
p.000002: Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements, and the applicable
p.000002: regulatory requirements.
p.000002: 1.16 Confidentiality
p.000002: Prevention of disclosure, to other than authorized individuals, of a sponsor's proprietary information or of
p.000002: a subject's identity.
p.000002: 1.17 Contract
p.000002: A written, dated, and signed agreement between two or more involved parties that sets out any arrangements on
p.000002: delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol
p.000002: may serve as the basis of a contract.
p.000002: 1.18 Coordinating Committee
p.000002: A committee that a sponsor may organize to coordinate the conduct of a multicentre trial.
p.000002: 1.19 Coordinating Investigator
p.000002: An investigator assigned the responsibility for the coordination of investigators at different centres
p.000002: participating in a multicentre trial.
p.000002:
p.000002:
p.000002:
p.000002:
p.000003: 3
p.000003:
p.000003: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000003:
p.000003: 1.20 Contract Research Organization (CRO)
p.000003: A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or
p.000003: more of a sponsor's trial-related duties and functions.
p.000003: 1.21 Direct Access
p.000003: Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a
p.000003: clinical trial. Any party (e.g., domestic and foreign regulatory authorities, sponsor's monitors and auditors)
p.000003: with direct access should take all reasonable precautions within the constraints of the applicable regulatory
p.000003: requirement(s) to maintain the confidentiality of subjects' identities and sponsor’s proprietary information.
p.000003: 1.22 Documentation
p.000003: All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records, and scans,
p.000003: x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors
p.000003: affecting a trial, and the actions taken.
p.000003: 1.23 Essential Documents
p.000003: Documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data
p.000003: produced (see 8. Essential Documents for the Conduct of a Clinical Trial).
p.000003: 1.24 Good Clinical Practice (GCP)
p.000003: A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical
p.000003: trials that provides assurance that the data and reported results are credible and accurate, and that the rights,
p.000003: integrity, and confidentiality of trial subjects are protected.
p.000003: 1.25 Independent Data-Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee,
p.000003: Data Monitoring Committee)
p.000003: An independent data-monitoring committee that may be established by the sponsor to assess at intervals the progress of
p.000003: a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to
p.000003: continue, modify, or stop a trial.
p.000003: 1.26 Impartial Witness
...
p.000012: investigational product(s), as described in the protocol, in the current Investigator's Brochure, in the
p.000012: product information and in other information sources provided by the sponsor.
p.000012:
p.000012: 4.1.3 The investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements.
p.000012:
p.000012: 4.1.4 The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by
p.000012: the appropriate regulatory authority(ies).
p.000012:
p.000012: 4.1.5 The investigator should maintain a list of appropriately qualified persons to whom the investigator
p.000012: has delegated significant trial-related duties.
p.000012:
p.000012: 4.2 Adequate Resources
p.000012:
p.000012: 4.2.1 The investigator should be able to demonstrate (e.g., based on retrospective data) a potential
p.000012: for recruiting the required number of suitable subjects within the agreed recruitment period.
p.000012:
p.000012: 4.2.2 The investigator should have sufficient time to properly conduct and complete the trial within the agreed
p.000012: trial period.
p.000012:
p.000012: 4.2.3 The investigator should have available an adequate number of qualified staff and adequate
p.000012: facilities for the foreseen duration of the trial to conduct the trial properly and safely.
p.000012:
p.000012: 4.2.4 The investigator should ensure that all persons assisting with the trial are adequately informed
p.000012: about the protocol, the investigational product(s), and their trial-related duties and functions.
p.000012:
p.000012: ADDENDUM
p.000012: 4.2.5 The investigator is responsible for supervising any individual or party to whom the investigator
p.000012: delegates trial-related duties and functions conducted at the trial site.
p.000012:
p.000012: 4.2.6 If the investigator/institution retains the services of any individual or party to perform
p.000012: trial-related duties and functions, the investigator/institution should ensure this individual or party is qualified
p.000012: to perform those trial-related duties and functions and should implement procedures to ensure the
p.000012: integrity of the trial-related duties and functions performed and any data generated.
p.000012:
p.000013: 13
p.000013:
p.000013: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000013:
p.000013: 4.3 Medical Care of Trial Subjects
p.000013:
p.000013: 4.3.1 A qualified physician (or dentist, when appropriate), who is an investigator or a sub-
p.000013: investigator for the trial, should be responsible for all trial-related medical (or dental) decisions.
p.000013:
p.000013: 4.3.2 During and following a subject's participation in a trial, the investigator/institution should ensure that
p.000013: adequate medical care is provided to a subject for any adverse events, including clinically
p.000013: significant laboratory values, related to the trial. The investigator/institution should
p.000013: inform a subject when medical care is needed for intercurrent illness(es) of which the investigator
p.000013: becomes aware.
p.000013:
p.000013: 4.3.3 It is recommended that the investigator inform the subject's primary physician about the subject's
p.000013: participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician
p.000013: being informed.
p.000013:
p.000013: 4.3.4 Although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the
p.000013: investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights.
p.000013:
p.000013: 4.4 Communication with IRB/IEC
p.000013:
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p.000021:
p.000021: 5.1.2 The sponsor is responsible for securing agreement from all involved parties to ensure direct
p.000021: access (see 1.21) to all trial related sites, source data/documents , and reports for the purpose of monitoring and
p.000021: auditing by the sponsor, and inspection by domestic and foreign regulatory authorities.
p.000021:
p.000021: 5.1.3 Quality control should be applied to each stage of data handling to ensure that all data are reliable and have
p.000021: been processed correctly.
p.000021:
p.000021: 5.1.4 Agreements, made by the sponsor with the investigator/institution and any other parties involved with the
p.000021: clinical trial, should be in writing, as part of the protocol or in a separate agreement.
p.000021:
p.000021: 5.2 Contract Research Organization (CRO)
p.000021:
p.000021: 5.2.1 A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the
p.000021: ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The CRO
p.000021: should implement quality assurance and quality control.
p.000021:
p.000021: 5.2.2 Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in
p.000021: writing.
p.000021:
p.000021:
p.000021:
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p.000021:
p.000022: 22
p.000022:
p.000022: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000022:
p.000022: ADDENDUM
p.000022: The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf, including
p.000022: trial-related duties and functions that are subcontracted to another party by the sponsor’s contracted CRO(s).
p.000022: 5.2.3 Any trial-related duties and functions not specifically transferred to and assumed by a CRO are
p.000022: retained by the sponsor.
p.000022:
p.000022: 5.2.4 All references to a sponsor in this guideline also apply to a CRO to the extent that a CRO has assumed the
p.000022: trial related duties and functions of a sponsor.
p.000022:
p.000022: 5.3 Medical Expertise
p.000022: The sponsor should designate appropriately qualified medical personnel who will be readily available to
p.000022: advise on trial related medical questions or problems. If necessary, outside consultant(s) may be appointed
p.000022: for this purpose.
p.000022: 5.4 Trial Design
p.000022:
p.000022: 5.4.1 The sponsor should utilize qualified individuals (e.g., biostatisticians, clinical
p.000022: pharmacologists, and physicians) as appropriate, throughout all stages of the trial process, from designing
p.000022: the protocol and CRFs and planning the analyses to analyzing and preparing interim and final clinical trial reports.
p.000022:
p.000022: 5.4.2 For further guidance: Clinical Trial Protocol and Protocol Amendment(s) (see 6.), the ICH Guideline
p.000022: for Structure and Content of Clinical Study Reports, and other appropriate ICH guidance on trial design, protocol and
p.000022: conduct.
p.000022:
p.000022: 5.5 Trial Management, Data Handling, and Record Keeping
p.000022:
p.000022: 5.5.1 The sponsor should utilize appropriately qualified individuals to supervise the overall conduct of
p.000022: the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the
p.000022: trial reports.
p.000022:
...
p.000049: (if not included in protocol or Investigator’s Brochure)
p.000049:
p.000049: SHIPPING RECORDS FOR INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALS
p.000049: To document instructions needed to ensure proper X X storage, packaging,
p.000049: dispensing and disposition of
p.000049: investigational products and trial-related materials
p.000049:
p.000049:
p.000049: To document shipment dates, batch numbers and X X method of shipment of
p.000049: investigational product(s)
p.000049: and trial-related materials. Allows tracking of product batch, review of shipping conditions, and
p.000049: accountability
p.000049:
p.000049:
p.000049:
p.000049:
p.000049:
p.000049:
p.000050: 50
p.000050:
p.000050: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000050:
p.000050:
p.000050: Title of Document
p.000050: Purpose
p.000050: Located in Files of
p.000050:
p.000050:
p.000050:
p.000050: 8.2.16
p.000050:
p.000050:
p.000050: CERTIFICATE(S) OF ANALYSIS OF INVESTIGATIONAL PRODUCT(S) SHIPPED
p.000050:
p.000050:
p.000050: To document identity, purity, and strength of investigational product(s) to be used in the trial
p.000050: Investigator/ Institution
p.000050: Sponsor
p.000050:
p.000050: X
p.000050:
p.000050:
p.000050:
p.000050: 8.2.17
p.000050: DECODING PROCEDURES FOR BLINDED TRIALS
p.000050: To document how, in case of an emergency, X identity of blinded investigational product
p.000050: can be
p.000050: revealed without breaking the blind for the remaining subjects' treatment
p.000050: X
p.000050: (third party if applicable)
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p.000051:
p.000051: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000051:
p.000051:
p.000051:
p.000051:
p.000051: Title of Document
p.000051: Purpose
p.000051: Located in Files of
p.000051:
p.000051:
p.000051:
p.000051: 8.2.18
p.000051:
p.000051:
p.000051: MASTER RANDOMISATION LIST
p.000051:
p.000051:
p.000051: To document method for randomisation of trial population
p.000051: Investigator/ Institution
p.000051: Sponsor
p.000051:
p.000051: X
p.000051: (third party if applicable)
p.000051:
p.000051:
p.000051:
p.000051: 8.2.19
p.000051:
p.000051: 8.2.20
p.000051: PRE-TRIAL MONITORING REPORT
p.000051:
p.000051: TRIAL INITIATION MONITORING REPORT
p.000051: To document that the site is suitable for the trial X (may be
p.000051: combined with 8.2.20)
p.000051:
p.000051: To document that trial procedures were reviewed X X with the investigator
p.000051: and the investigator’s trial
p.000051: staff ( may be combined with 8.2.19)
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p.000052:
p.000052: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000052:
p.000052:
p.000052: 8.3 During the Clinical Conduct of the Trial
p.000052: In addition to having on file the above documents, the following should be added to the files during the trial as
p.000052: evidence that all new relevant information is documented as it becomes available
p.000052:
p.000052:
p.000052:
p.000052: Title of Document
p.000052: Purpose
p.000052: Located in Files of
p.000052:
p.000052:
p.000052:
p.000052: 8.3.1
p.000052:
p.000052:
p.000052: 8.3.2
p.000052:
p.000052:
p.000052: INVESTIGATOR’S BROCHURE UPDATES
p.000052:
p.000052:
p.000052: ANY REVISION TO:
p.000052: - protocol/amendment(s) and CRF
p.000052: - informed consent form
p.000052: - any other written information provided to subjects
p.000052: - advertisement for subject recruitment (if used)
p.000052:
p.000052:
...
Political / vulnerable
Searching for indicator vulnerable:
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p.000006: Detailed, written instructions to achieve uniformity of the performance of a specific function.
p.000006: 1.56 Subinvestigator
p.000006: Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to
p.000006: perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates,
p.000006: residents, research fellows). See also Investigator.
p.000006: 1.57 Subject/Trial Subject
p.000006: An individual who participates in a clinical trial, either as a recipient of the investigational
p.000006: product(s) or as a control.
p.000006:
p.000006:
p.000006:
p.000006:
p.000007: 7
p.000007:
p.000007: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000007:
p.000007: 1.58 Subject Identification Code
p.000007: A unique identifier assigned by the investigator to each trial subject to protect the subject's identity
p.000007: and used in lieu of the subject's name when the investigator reports adverse events and/or other trial
p.000007: related data.
p.000007: 1.59 Trial Site
p.000007: The location(s) where trial-related activities are actually conducted.
p.000007: 1.60 Unexpected Adverse Drug Reaction
p.000007: An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g.,
p.000007: Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics
p.000007: for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for
p.000007: Expedited Reporting).
p.000007:
p.000007: 1.61 Vulnerable Subjects
p.000007: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether
p.000007: justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a
p.000007: hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure,
p.000007: such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees
p.000007: of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable
p.000007: subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons,
p.000007: patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and
p.000007: those incapable of giving consent.
p.000007: 1.62 Well-being (of the trial subjects)
p.000007: The physical and mental integrity of the subjects participating in a clinical trial.
p.000007: ADDENDUM
p.000007: 1.63 Certified Copy
p.000007: A copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated
p.000007: signature or by generation through a validated process) to have the same information, including data that describe the
p.000007: context, content, and structure, as the original.
p.000007: 1.64 Monitoring Plan
p.000007: A document that describes the strategy, methods, responsibilities, and requirements for monitoring
p.000007: the trial.
p.000007: 1.65 Validation of Computerized Systems
p.000007: A process of establishing and documenting that the specified requirements of a computerized system can be
p.000007: consistently fulfilled from design until decommissioning of the system or transition to a new system. The
p.000007: approach to validation should be based on a risk assessment that takes into consideration the intended use of the
...
p.000008: participation.
p.000008:
p.000008: 2.10 All clinical trial information should be recorded, handled, and stored in a way that allows its accurate
p.000008: reporting, interpretation and verification.
p.000008: ADDENDUM
p.000008: This principle applies to all records referenced in this guideline, irrespective of the type of media used.
p.000008: 2.11 The confidentiality of records that could identify subjects should be protected, respecting the privacy and
p.000008: confidentiality rules in accordance with the applicable regulatory requirement(s).
p.000008:
p.000008: 2.12 Investigational products should be manufactured, handled, and stored in accordance with applicable good
p.000008: manufacturing practice (GMP). They should be used in accordance with the approved protocol.
p.000008:
p.000008:
p.000008:
p.000008:
p.000008:
p.000009: 9
p.000009:
p.000009: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000009:
p.000009: 2.13 Systems with procedures that assure the quality of every aspect of the trial should be
p.000009: implemented.
p.000009: ADDENDUM
p.000009: Aspects of the trial that are essential to ensure human subject protection and reliability of trial results should be
p.000009: the focus of such systems.
p.000009:
p.000009: 3. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)
p.000009:
p.000009: 3.1 Responsibilities
p.000009:
p.000009: 3.1.1 An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects. Special
p.000009: attention should be paid to trials that may include vulnerable subjects.
p.000009:
p.000009: 3.1.2 The IRB/IEC should obtain the following documents:
p.000009: trial protocol(s)/amendment(s), written informed consent form(s) and consent form updates that the investigator
p.000009: proposes for use in the trial, subject recruitment procedures (e.g., advertisements), written information to be
p.000009: provided to subjects, Investigator's Brochure (IB), available safety information, information about
p.000009: payments and compensation available to subjects, the investigator’s current curriculum vitae and/or
p.000009: other documentation evidencing qualifications, and any other documents that the IRB/IEC may need to
p.000009: fulfil its responsibilities.
p.000009: The IRB/IEC should review a proposed clinical trial within a reasonable time and document its views in
p.000009: writing, clearly identifying the trial, the documents reviewed and the dates for the following:
p.000009: - approval/favourable opinion;
p.000009: - modifications required prior to its approval/favourable opinion;
p.000009: - disapproval / negative opinion; and
p.000009: - termination/suspension of any prior approval/favourable opinion.
p.000009:
p.000009: 3.1.3 The IRB/IEC should consider the qualifications of the investigator for the proposed trial, as documented by a
p.000009: current curriculum vitae and/or by any other relevant documentation the IRB/IEC requests.
p.000009:
...
Health / Cognitive Impairment
Searching for indicator impaired:
(return to top)
p.000039: described under the following headings where appropriate:
p.000039:
p.000039:
p.000040: 40
p.000040:
p.000040: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000040:
p.000040: - Single dose
p.000040: - Repeated dose
p.000040: - Carcinogenicity
p.000040: - Special studies (e.g., irritancy and sensitisation)
p.000040: - Reproductive toxicity
p.000040: - Genotoxicity (mutagenicity)
p.000040: 7.3.6 Effects in Humans Introduction:
p.000040: A thorough discussion of the known effects of the investigational product(s) in humans should be provided,
p.000040: including information on pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy,
p.000040: and other pharmacological activities. Where possible, a summary of each completed clinical trial should be
p.000040: provided. Information should also be provided regarding results of any use of the investigational product(s) other
p.000040: than from in clinical trials, such as from experience during marketing.
p.000040: (a) Pharmacokinetics and Product Metabolism in Humans
p.000040: - A summary of information on the pharmacokinetics of the investigational product(s) should be
p.000040: presented, including the following, if available:
p.000040: - Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, distribution, and
p.000040: elimination).
p.000040: - Bioavailability of the investigational product (absolute, where possible, and/or relative) using a
p.000040: reference dosage form.
p.000040: - Population subgroups (e.g., gender, age, and impaired organ function).
p.000040: - Interactions (e.g., product-product interactions and effects of food).
p.000040: - Other pharmacokinetic data (e.g., results of population studies performed within clinical trial(s).
p.000040: (b) Safety and Efficacy
p.000040: A summary of information should be provided about the investigational product's/products'
p.000040: (including metabolites, where appropriate) safety, pharmacodynamics, efficacy, and dose response that were obtained
p.000040: from preceding trials in humans (healthy volunteers and/or patients). The implications of this information should be
p.000040: discussed. In cases where a number of clinical trials have been completed, the use of summaries of safety
p.000040: and efficacy across multiple trials by indications in subgroups may provide a clear presentation of the data. Tabular
p.000040: summaries of adverse drug reactions for all the clinical trials (including those for all the studied
p.000040: indications) would be useful. Important differences in adverse drug reaction patterns/incidences across indications
p.000040: or subgroups should be discussed.
p.000040: The IB should provide a description of the possible risks and adverse drug reactions to be anticipated on the basis
p.000040: of prior experiences with the product under investigation and with related products. A description should also
p.000040: be provided of the precautions or special monitoring to be done as part of the investigational use of the product(s).
p.000040: (c) Marketing Experience
...
Health / Drug Usage
Searching for indicator drug:
(return to top)
p.000015: 4.8 Informed Consent of Trial Subjects
p.000016: 16
p.000016: 4.9 Records and Reports
p.000019: 19
p.000019: 4.10 Progress Reports
p.000019: 19
p.000019: 4.11 Safety Reporting
p.000020: 20
p.000020: 4.12 Premature Termination or Suspension of a Trial
p.000020: 20
p.000020: 4.13 Final Report(s) by Investigator
p.000020: 20
p.000020: 5. SPONSOR
p.000021: 21
p.000021: 5.0 Quality Management
p.000021: 21
p.000021: 5.1 Quality Assurance and Quality Control
p.000022: 22
p.000022: 5.2 Contract Research Organization (CRO)
p.000022: 22
p.000022: 5.3 Medical Expertise
p.000023: 23
p.000023: i
p.000023:
p.000023: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000023: 5.4 Trial Design
p.000023: 23
p.000023: 5.5 Trial Management, Data Handling, and Record Keeping 23
p.000023: 5.6 Investigator Selection
p.000025: 25
p.000025: 5.7 Allocation of Responsibilities
p.000025: 25
p.000025: 5.8 Compensation to Subjects and Investigators
p.000025: 25
p.000025: 5.9 Financing
p.000026: 26
p.000026: 5.10 Notification/Submission to Regulatory Authority(ies)
p.000026: 26
p.000026: 5.11 Confirmation of Review by IRB/IEC
p.000026: 26
p.000026: 5.12 Information on Investigational Product(s)
p.000026: 26
p.000026: 5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s) 27
p.000026: 5.14 Supplying and Handling Investigational Product(s)
p.000027: 27
p.000027: 5.15 Record Access
p.000028: 28
p.000028: 5.16 Safety Information
p.000028: 28
p.000028: 5.17 Adverse Drug Reaction Reporting
p.000028: 28
p.000028: 5.18 Monitoring
p.000029: 29
p.000029: 5.18.1 Purpose
p.000029: 29
p.000029: 5.18.2 Selection and Qualifications of Monitors 29
p.000029: 5.18.3 Extent and Nature of Monitoring
p.000029: 29
p.000029: 5.18.5 Monitoring Procedures
p.000031: 31
p.000031: 5.18.6 Monitoring Report
p.000032: 32
p.000032: 5.18.7 Monitoring Plan
p.000032: 32
p.000032: 5.19 Audit
p.000032: 32
p.000032: 5.19.1 Purpose
p.000032: 32
p.000032: 5.19.2 Selection and Qualification of Auditors 32
p.000032: 5.19.3 Auditing Procedures
p.000033: 33
p.000033: 5.20 Noncompliance
p.000033: 33
p.000033: 5.21 Premature Termination or Suspension of a Trial
p.000033: 33
p.000033: 5.22 Clinical Trial/Study Reports
p.000033: 33
p.000033: 5.23 Multicentre Trials
p.000034: 34
p.000034: 6. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S) 34
p.000034: 6.1 General Information
p.000034: 34
p.000034: 6.2 Background Information
p.000035: 35
p.000035: 6.3 Trial Objectives and Purpose
p.000035: 35
p.000035: 6.4 Trial Design
p.000035: 35
p.000035: 6.5 Selection and Withdrawal of Subjects
p.000036: 36
p.000036: 6.6 Treatment of Subjects
p.000036: 36
p.000036: 6.7 Assessment of Efficacy
p.000036: 36
p.000036: ii
p.000036:
p.000036: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000036: 6.8 Assessment of Safety
p.000036: 36
p.000036: 6.9 Statistics
p.000037: 37
p.000037: 6.10 Direct Access to Source Data/Documents
p.000037: 37
p.000037: 6.11 Quality Control and Quality Assurance
p.000037: 37
...
p.000059: other approaches. For example, centralized monitoring can now offer a greater advantage, to a broader
p.000059: range of trials than is suggested in the original text. Therefore, this guideline has been amended to
p.000059: encourage implementation of improved and more efficient approaches to clinical trial design, conduct,
p.000059: oversight, recording and reporting while continuing to ensure human subject protection and reliability of trial
p.000059: results. Standards regarding electronic records and essential documents intended to increase clinical trial quality
p.000059: and efficiency have also been updated.
p.000059: This guideline should be read in conjunction with other ICH guidelines relevant to the conduct of
p.000059: clinical trials (e.g., E2A (clinical safety data management), E3 (clinical study reporting), E7 (geriatric
p.000059: populations), E8 (general considerations for clinical trials), E9 (statistical principles), and E11 (pediatric
p.000059: populations)).
p.000059: This ICH GCP Guideline Integrated Addendum provides a unified standard for the European Union, Japan, the United
p.000059: States, Canada, and Switzerland to facilitate the mutual acceptance of data from clinical trials by the regulatory
p.000059: authorities in these jurisdictions. In the event of any conflict between the E6(R1) text and the E6(R2) addendum text,
p.000059: the E6(R2) addendum text should take priority.
p.000059:
p.000059:
p.000059:
p.000059:
p.000001: 1
p.000001:
p.000001: 1. GLOSSARY
p.000001:
p.000001: 1.1 Adverse Drug Reaction (ADR)
p.000001: In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as
p.000001: the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal
p.000001: product related to any dose should be considered adverse drug reactions. The phrase responses to a medicinal
p.000001: product means that a causal relationship between a medicinal product and an adverse event is at least a reasonable
p.000001: possibility, i.e., the relationship cannot be ruled out.
p.000001: Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at
p.000001: doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of
p.000001: physiological function (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for
p.000001: Expedited Reporting).
p.000001: 1.2 Adverse Event (AE)
p.000001: Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical
p.000001: product and which does not necessarily have a causal relationship with this treatment. An adverse event
p.000001: (AE) can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom,
p.000001: or disease temporally associated with the use of a medicinal (investigational) product, whether or not
p.000001: related to the medicinal (investigational) product (see the ICH Guideline for Clinical Safety
p.000001: Data Management: Definitions and Standards for Expedited Reporting).
p.000001: 1.3 Amendment (to the protocol)
p.000001: See Protocol Amendment.
p.000001: 1.4 Applicable Regulatory Requirement(s)
p.000001: Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products.
p.000001: 1.5 Approval (in relation to Institutional Review Boards)
p.000001: The affirmative decision of the IRB that the clinical trial has been reviewed and may be conducted at
p.000001: the institution site within the constraints set forth by the IRB, the institution, Good Clinical Practice (GCP), and
p.000001: the applicable regulatory requirements.
p.000001: 1.6 Audit
p.000001: A systematic and independent examination of trial related activities and documents to determine whether the evaluated
...
p.000005: trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other
p.000005: protocol referenced documents. Throughout the ICH GCP Guideline the term protocol refers to protocol and protocol
p.000005: amendments.
p.000005: 1.45 Protocol Amendment
p.000005: A written description of a change(s) to or formal clarification of a protocol.
p.000005: 1.46 Quality Assurance (QA)
p.000005: All those planned and systematic actions that are established to ensure that the trial is performed and the data are
p.000005: generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the
p.000005: applicable regulatory requirement(s).
p.000005: 1.47 Quality Control (QC)
p.000005: The operational techniques and activities undertaken within the quality assurance system to verify that the
p.000005: requirements for quality of the trial-related activities have been fulfilled.
p.000005: 1.48 Randomization
p.000005: The process of assigning trial subjects to treatment or control groups using an element of chance to determine the
p.000005: assignments in order to reduce bias.
p.000005: 1.49 Regulatory Authorities
p.000005: Bodies having the power to regulate. In the ICH GCP Guideline the expression Regulatory Authorities
p.000005: includes the authorities that review submitted clinical data and those that conduct inspections (see 1.29).
p.000005: These bodies are sometimes referred to as competent authorities.
p.000005:
p.000005:
p.000005:
p.000005:
p.000006: 6
p.000006:
p.000006: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000006:
p.000006: 1.50 Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)
p.000006: Any untoward medical occurrence that at any dose:
p.000006: - results in death,
p.000006: - is life-threatening,
p.000006: - requires inpatient hospitalization or prolongation of existing hospitalization,
p.000006: - results in persistent or significant disability/incapacity, or
p.000006: - is a congenital anomaly/birth defect
p.000006: (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited
p.000006: Reporting).
p.000006: 1.51 Source Data
p.000006: All information in original records and certified copies of original records of clinical findings, observations, or
p.000006: other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are
p.000006: contained in source documents (original records or certified copies).
p.000006: 1.52 Source Documents
p.000006: Original documents, data, and records (e.g., hospital records, clinical and office charts,
p.000006: laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records,
p.000006: recorded data from automated instruments, copies or transcriptions certified after verification as being
p.000006: accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files,
p.000006: and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical
p.000006: trial).
p.000006: 1.53 Sponsor
p.000006: An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or
p.000006: financing of a clinical trial.
p.000006: 1.54 Sponsor-Investigator
p.000006: An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate
p.000006: direction the investigational product is administered to, dispensed to, or used by a subject. The term does not
p.000006: include any person other than an individual (e.g., it does not include a corporation or an agency). The
p.000006: obligations of a sponsor-investigator include both those of a sponsor and those of an investigator.
p.000006: 1.55 Standard Operating Procedures (SOPs)
p.000006: Detailed, written instructions to achieve uniformity of the performance of a specific function.
p.000006: 1.56 Subinvestigator
p.000006: Any individual member of the clinical trial team designated and supervised by the investigator at a trial site to
p.000006: perform critical trial-related procedures and/or to make important trial-related decisions (e.g., associates,
p.000006: residents, research fellows). See also Investigator.
p.000006: 1.57 Subject/Trial Subject
p.000006: An individual who participates in a clinical trial, either as a recipient of the investigational
p.000006: product(s) or as a control.
p.000006:
p.000006:
p.000006:
p.000006:
p.000007: 7
p.000007:
p.000007: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000007:
p.000007: 1.58 Subject Identification Code
p.000007: A unique identifier assigned by the investigator to each trial subject to protect the subject's identity
p.000007: and used in lieu of the subject's name when the investigator reports adverse events and/or other trial
p.000007: related data.
p.000007: 1.59 Trial Site
p.000007: The location(s) where trial-related activities are actually conducted.
p.000007: 1.60 Unexpected Adverse Drug Reaction
p.000007: An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g.,
p.000007: Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics
p.000007: for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for
p.000007: Expedited Reporting).
p.000007:
p.000007: 1.61 Vulnerable Subjects
p.000007: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether
p.000007: justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a
p.000007: hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure,
p.000007: such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees
p.000007: of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable
p.000007: subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons,
...
p.000011:
p.000011: 3.3.4 Determining the frequency of continuing review, as appropriate.
p.000011:
p.000011: 3.3.5 Providing, according to the applicable regulatory requirements, expedited review and
p.000011: approval/favourable opinion of minor change(s) in ongoing trials that have the approval/favourable
p.000011: opinion of the IRB/IEC.
p.000011:
p.000011: 3.3.6 Specifying that no subject should be admitted to a trial before the IRB/IEC issues its written
p.000011: approval/favourable opinion of the trial.
p.000011:
p.000011: 3.3.7 Specifying that no deviations from, or changes of, the protocol should be initiated without
p.000011: prior written IRB/IEC approval/favourable opinion of an appropriate amendment, except when
p.000011: necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or
p.000011: administrative aspects of the trial (e.g., change of monitor(s), telephone number(s)) (see 4.5.2).
p.000011:
p.000011: 3.3.8 Specifying that the investigator should promptly report to the IRB/IEC:
p.000011: (a) Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial subjects (see 3.3.7,
p.000011: 4.5.2, 4.5.4).
p.000011: (b) Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial (see 4.10.2).
p.000011: (c) All adverse drug reactions (ADRs) that are both serious and unexpected.
p.000011: (d) New information that may affect adversely the safety of the subjects or the conduct of the trial.
p.000011:
p.000011: 3.3.9 Ensuring that the IRB/IEC promptly notify in writing the investigator/institution
p.000011: concerning:
p.000011: (a) Its trial-related decisions/opinions.
p.000011: (b) The reasons for its decisions/opinions.
p.000011: (c) Procedures for appeal of its decisions/opinions.
p.000011:
p.000011: 3.4 Records
p.000011: The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists, lists of
p.000011: occupations/affiliations of members, submitted documents, minutes of meetings, and correspondence) for
p.000011: a period of at least 3-years after completion of the trial and make them available upon request from the
p.000011: regulatory authority(ies).
p.000011: The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its written
p.000011: procedures and membership lists.
p.000011:
p.000011:
p.000011:
p.000011:
p.000011:
p.000011:
p.000012: 12
p.000012:
p.000012: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000012:
p.000012: 4. INVESTIGATOR
p.000012:
p.000012: 4.1 Investigator's Qualifications and Agreements
p.000012:
p.000012: 4.1.1 The investigator(s) should be qualified by education, training, and experience to assume responsibility for
p.000012: the proper conduct of the trial, should meet all the qualifications specified by the applicable
p.000012: regulatory requirement(s), and should provide evidence of such qualifications through up-to-date
...
p.000018:
p.000018: 4.9.7 Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the
p.000018: investigator/institution should make available for direct access all requested trial-related records.
p.000018:
p.000018: 4.10 Progress Reports
p.000018:
p.000018: 4.10.1 The investigator should submit written summaries of the trial status to the IRB/IEC annually, or
p.000018: more frequently, if requested by the IRB/IEC.
p.000018:
p.000019: 19
p.000019:
p.000019: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000019:
p.000019: 4.10.2 The investigator should promptly provide written reports to the sponsor, the IRB/IEC (see 3.3.8)
p.000019: and, where applicable, the institution on any changes significantly affecting the conduct of the trial, and/or
p.000019: increasing the risk to subjects.
p.000019:
p.000019: 4.11 Safety Reporting
p.000019:
p.000019: 4.11.1 All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that
p.000019: the protocol or other document (e.g., Investigator's Brochure) identifies as not needing immediate reporting.
p.000019: The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up
p.000019: reports should identify subjects by unique code numbers assigned to the trial subjects rather than by the subjects'
p.000019: names, personal identification numbers, and/or addresses. The investigator should also comply with the
p.000019: applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to
p.000019: the regulatory authority(ies) and the IRB/IEC.
p.000019:
p.000019: 4.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety
p.000019: evaluations should be reported to the sponsor according to the reporting requirements and within
p.000019: the time periods specified by the sponsor in the protocol.
p.000019:
p.000019: 4.11.3 For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any additional requested
p.000019: information (e.g., autopsy reports and terminal medical reports).
p.000019:
p.000019: 4.12 Premature Termination or Suspension of a Trial
p.000019: If the trial is prematurely terminated or suspended for any reason, the investigator/institution should
p.000019: promptly inform the trial subjects, should assure appropriate therapy and follow-up for the subjects, and, where
p.000019: required by the applicable regulatory requirement(s), should inform the regulatory authority(ies). In addition:
p.000019:
p.000019: 4.12.1 If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator
p.000019: should inform the institution where applicable, and the investigator/institution should promptly
p.000019: inform the sponsor and the IRB/IEC, and should provide the sponsor and the IRB/IEC a detailed written explanation of
p.000019: the termination or suspension.
p.000019:
p.000019: 4.12.2 If the sponsor terminates or suspends a trial (see 5.21), the investigator should promptly inform the
p.000019: institution where applicable and the investigator/institution should promptly inform the IRB/IEC and provide the
...
p.000027: specifications, should this become necessary, and maintain records of batch sample analyses and
p.000027: characteristics. To the extent stability permits, samples should be retained either until the analyses of
p.000027: the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the
p.000027: longer retention period.
p.000027:
p.000027: 5.15 Record Access
p.000027:
p.000027: 5.15.1 The sponsor should ensure that it is specified in the protocol or other written agreement that the
p.000027: investigator(s)/institution(s) provide direct access to source data/documents for trial-related monitoring, audits,
p.000027: IRB/IEC review, and regulatory inspection.
p.000027:
p.000027: 5.15.2 The sponsor should verify that each subject has consented, in writing, to direct access to his/her original
p.000027: medical records for trial-related monitoring, audit, IRB/IEC review, and regulatory inspection.
p.000027:
p.000027: 5.16 Safety Information
p.000027:
p.000027: 5.16.1 The sponsor is responsible for the ongoing safety evaluation of the investigational product(s).
p.000027:
p.000027: 5.16.2 The sponsor should promptly notify all concerned investigator(s)/institution(s) and the regulatory
p.000027: authority(ies) of findings that could affect adversely the safety of subjects, impact the conduct of the
p.000027: trial, or alter the IRB/IEC's approval/favourable opinion to continue the trial.
p.000027:
p.000027: 5.17 Adverse Drug Reaction Reporting
p.000027:
p.000027: 5.17.1 The sponsor should expedite the reporting to all concerned investigator(s)/institutions(s), to the
p.000027: IRB(s)/IEC(s), where required, and to the regulatory authority(ies) of all adverse drug reactions (ADRs) that are both
p.000027: serious and unexpected.
p.000027:
p.000027: 5.17.2 Such expedited reports should comply with the applicable regulatory requirement(s) and with the ICH Guideline
p.000027: for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.
p.000027:
p.000027: 5.17.3 The sponsor should submit to the regulatory authority(ies) all safety updates and periodic reports, as required
p.000027: by applicable regulatory requirement(s).
p.000027:
p.000027:
p.000027:
p.000028: 28
p.000028:
p.000028: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000028:
p.000028:
p.000028: 5.18 Monitoring
p.000028:
p.000028: 5.18.1 Purpose
p.000028: The purposes of trial monitoring are to verify that:
p.000028: (a) The rights and well-being of human subjects are protected.
p.000028: (b) The reported trial data are accurate, complete, and verifiable from source documents.
p.000028: (c) The conduct of the trial is in compliance with the currently approved
p.000028: protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).
p.000028:
p.000028: 5.18.2 Selection and Qualifications of Monitors
p.000028: (a) Monitors should be appointed by the sponsor.
p.000028: (b) Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge
p.000028: needed to monitor the trial adequately. A monitor’s qualifications should be documented.
p.000028: (c) Monitors should be thoroughly familiar with the investigational product(s), the protocol, written
p.000028: informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs,
...
p.000040: than from in clinical trials, such as from experience during marketing.
p.000040: (a) Pharmacokinetics and Product Metabolism in Humans
p.000040: - A summary of information on the pharmacokinetics of the investigational product(s) should be
p.000040: presented, including the following, if available:
p.000040: - Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, distribution, and
p.000040: elimination).
p.000040: - Bioavailability of the investigational product (absolute, where possible, and/or relative) using a
p.000040: reference dosage form.
p.000040: - Population subgroups (e.g., gender, age, and impaired organ function).
p.000040: - Interactions (e.g., product-product interactions and effects of food).
p.000040: - Other pharmacokinetic data (e.g., results of population studies performed within clinical trial(s).
p.000040: (b) Safety and Efficacy
p.000040: A summary of information should be provided about the investigational product's/products'
p.000040: (including metabolites, where appropriate) safety, pharmacodynamics, efficacy, and dose response that were obtained
p.000040: from preceding trials in humans (healthy volunteers and/or patients). The implications of this information should be
p.000040: discussed. In cases where a number of clinical trials have been completed, the use of summaries of safety
p.000040: and efficacy across multiple trials by indications in subgroups may provide a clear presentation of the data. Tabular
p.000040: summaries of adverse drug reactions for all the clinical trials (including those for all the studied
p.000040: indications) would be useful. Important differences in adverse drug reaction patterns/incidences across indications
p.000040: or subgroups should be discussed.
p.000040: The IB should provide a description of the possible risks and adverse drug reactions to be anticipated on the basis
p.000040: of prior experiences with the product under investigation and with related products. A description should also
p.000040: be provided of the precautions or special monitoring to be done as part of the investigational use of the product(s).
p.000040: (c) Marketing Experience
p.000040: The IB should identify countries where the investigational product has been marketed or approved. Any significant
p.000040: information arising from the marketed use should be summarised (e.g., formulations, dosages, routes
p.000040: of administration, and adverse product reactions). The IB should also identify all the countries where the
p.000040: investigational product
p.000040:
p.000040:
p.000041: 41
p.000041:
p.000041: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000041:
p.000041: did not receive approval/registration for marketing or was withdrawn from
p.000041: marketing/registration.
p.000041:
p.000041: 7.3.7 Summary of Data and Guidance for the Investigator
p.000041: This section should provide an overall discussion of the nonclinical and clinical data, and should summarise the
p.000041: information from various sources on different aspects of the investigational product(s), wherever possible.
p.000041: In this way, the investigator can be provided with the most informative interpretation of the available
p.000041: data and with an assessment of the implications of the information for future clinical trials.
p.000041: Where appropriate, the published reports on related products should be discussed. This could help the investigator
p.000041: to anticipate adverse drug reactions or other problems in clinical trials.
p.000041: The overall aim of this section is to provide the investigator with a clear understanding of the possible risks and
p.000041: adverse reactions, and of the specific tests, observations, and precautions that may be needed for a clinical
p.000041: trial. This understanding should be based on the available physical, chemical, pharmaceutical,
p.000041: pharmacological, toxicological, and clinical information on the investigational product(s). Guidance should also be
p.000041: provided to the clinical investigator on the recognition and treatment of possible overdose and adverse drug reactions
p.000041: that is based on previous human experience and on the pharmacology of the investigational product.
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000041:
p.000042: 42
p.000042:
p.000042: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000042:
p.000042:
p.000042: 7.4 APPENDIX 1:
p.000042: TITLE PAGE (Example)
p.000042: SPONSOR'S NAME
p.000042: Product:
p.000042: Research Number:
p.000042: Name(s): Chemical, Generic (if approved)
p.000042: Trade Name(s) (if legally permissible and desired by the sponsor)
p.000042:
p.000042: INVESTIGATOR'S BROCHURE
p.000042:
p.000042: Edition Number:
p.000042: Release Date:
p.000042:
p.000042:
p.000042:
p.000042: Replaces Previous Edition Number: Date:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000042:
p.000043: 43
p.000043:
p.000043: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000043:
p.000043:
p.000043: 7.5 APPENDIX 2:
p.000043: TABLE OF CONTENTS OF INVESTIGATOR'S BROCHURE (Example)
p.000043:
p.000043: - Confidentiality Statement (optional)
...
p.000055:
p.000055: To document the existence of the subject and substantiate integrity of trial data collected. To include
p.000055: original documents related to the trial, to medical treatment, and history of subject
p.000055:
p.000055: To document that the investigator or authorised member of the investigator’s staff confirms the
p.000055: observations recorded
p.000055:
p.000055: To document all changes/additions or corrections made to CRF after initial data were recorded
p.000055:
p.000055: Notification by originating investigator to sponsor of serious adverse events and related reports in accordance
p.000055: with 4.11
p.000055: X
p.000055:
p.000055:
p.000055:
p.000055: X
p.000055:
p.000055:
p.000055:
p.000055: X
p.000055: (copy)
p.000055:
p.000055: X
p.000055: (copy) X
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055: X
p.000055: (original)
p.000055:
p.000055: X
p.000055: (original) X
p.000055:
p.000055:
p.000056: 56
p.000056:
p.000056: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000056:
p.000056:
p.000056: Title of Document
p.000056: Purpose
p.000056: Located in Files of
p.000056:
p.000056:
p.000056:
p.000056: 8.3.17
p.000056:
p.000056:
p.000056:
p.000056:
p.000056:
p.000056: 8.3.18
p.000056:
p.000056:
p.000056: 8.3.19
p.000056:
p.000056:
p.000056: 8.3.20
p.000056:
p.000056:
p.000056: 8.3.21
p.000056:
p.000056:
p.000056: NOTIFICATION BY SPONSOR AND/OR INVESTIGATOR, WHERE APPLICABLE, TO REGULATORY AUTHORITY(IES) AND IRB(S)/IEC(S) OF
p.000056: UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS AND OF OTHER SAFETY INFORMATION
p.000056:
p.000056: NOTIFICATION BY SPONSOR TO INVESTIGATORS OF SAFETY INFORMATION
p.000056:
p.000056: INTERIM OR ANNUAL REPORTS TO IRB/IEC AND AUTHORITY(IES)
p.000056:
p.000056: SUBJECT SCREENING LOG
p.000056:
p.000056:
p.000056: SUBJECT IDENTIFICATION CODE LIST
p.000056:
p.000056:
p.000056: Notification by sponsor and/or investigator, where applicable, to regulatory authorities and
p.000056: IRB(s)/IEC(s) of unexpected serious adverse drug reactions in accordance with 5.17 and 4.11.1 and of other
p.000056: safety information in accordance with
p.000056: 5.16.2 and 4.11.2
p.000056:
p.000056: Notification by sponsor to investigators of safety information in accordance with 5.16.2
p.000056:
p.000056: Interim or annual reports provided to IRB/IEC in accordance with 4.10 and to authority(ies) in
p.000056: accordance with 5.17.3
p.000056:
p.000056: To document identification of subjects who entered pre-trial screening
p.000056:
p.000056: To document that investigator/institution keeps a confidential list of names of all subjects allocated to trial
p.000056: numbers on enrolling in the trial. Allows investigator/institution to reveal identity of any subject
p.000056: Investigator/ Institution
p.000056: X
p.000056: (where required)
p.000056:
p.000056:
p.000056:
p.000056: X
p.000056:
p.000056:
p.000056: X
p.000056:
p.000056:
p.000056: X
p.000056:
p.000056:
p.000056: X
p.000056: Sponsor
p.000056:
p.000056: X
p.000056:
p.000056:
p.000056:
p.000056:
p.000056:
p.000056: X
p.000056:
p.000056:
p.000056: X
p.000056: (where required)
p.000056:
p.000056: X
p.000056: (where required)
p.000056:
p.000056:
p.000056:
p.000056:
p.000056:
p.000056:
p.000056:
p.000057: 57
p.000057:
p.000057: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000057:
p.000057:
p.000057: Title of Document
p.000057: Purpose
p.000057: Located in Files of
p.000057:
p.000057:
p.000057:
p.000057: 8.3.22
p.000057:
p.000057:
p.000057: SUBJECT ENROLMENT LOG
p.000057:
p.000057:
p.000057: To document chronological enrolment of subjects by trial number
p.000057: Investigator/ Institution
p.000057: X
p.000057: Sponsor
p.000057:
p.000057:
p.000057:
p.000057:
...
Searching for indicator influence:
(return to top)
p.000015:
p.000015: 4.8.1 In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory
p.000015: requirement(s), and should adhere to GCP and to the ethical principles that have their origin in the
p.000015: Declaration of Helsinki. Prior to the beginning of the trial, the investigator should have the IRB/IEC's written
p.000015: approval/favourable opinion of the written informed consent form and any other written information to be provided to
p.000015: subjects.
p.000015:
p.000015: 4.8.2 The written informed consent form and any other written information to be provided to subjects should be
p.000015: revised whenever important new information becomes available that may be relevant to the subject’s consent. Any revised
p.000015: written informed consent form, and written information should receive the IRB/IEC's approval/favourable opinion in
p.000015: advance of use. The subject or the subject’s legally acceptable representative should be informed in a timely manner
p.000015: if new information becomes available that may be relevant to the subject’s willingness to continue
p.000015: participation in the trial. The communication of this information should be documented.
p.000015:
p.000015: 4.8.3 Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or
p.000015: to continue to participate in a trial.
p.000015:
p.000015: 4.8.4 None of the oral and written information concerning the trial, including the written informed
p.000015: consent form, should contain any language that causes the subject or the subject's legally acceptable
p.000015: representative to waive or to appear to waive any legal rights, or that releases or appears to release the
p.000015: investigator, the institution, the sponsor, or their agents from liability for negligence.
p.000015:
p.000015: 4.8.5 The investigator, or a person designated by the investigator, should fully inform the subject or,
p.000015: if the subject is unable to provide informed consent, the subject's legally acceptable representative, of
p.000015: all pertinent aspects of the trial including the written information and the approval/ favourable opinion by
p.000015: the IRB/IEC.
p.000015:
p.000015: 4.8.6 The language used in the oral and written information about the trial, including the written
p.000015: informed consent form, should be as non-technical as practical and should be understandable to the
p.000015: subject or the subject's legally acceptable representative and the impartial witness, where applicable.
p.000015:
p.000015: 4.8.7 Before informed consent may be obtained, the investigator, or a person designated by the investigator, should
...
Searching for indicator substance:
(return to top)
p.000038: The sponsor may wish to include a statement instructing the investigator/recipients to treat the IB as a
p.000038: confidential document for the sole information and use of the investigator's team and the IRB/IEC.
p.000038:
p.000038: 7.3 Contents of the Investigator’s Brochure
p.000038: The IB should contain the following sections, each with literature references where appropriate:
p.000038:
p.000038: 7.3.1 Table of Contents
p.000038:
p.000038: An example of the Table of Contents is given in Appendix 2
p.000038:
p.000038: 7.3.2 Summary
p.000038:
p.000038: A brief summary (preferably not exceeding two pages) should be given, highlighting the significant physical,
p.000038: chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical
p.000038: information available that is relevant to the stage of clinical development of the investigational product.
p.000038:
p.000038: 7.3.3 Introduction
p.000038:
p.000038: A brief introductory statement should be provided that contains the chemical name (and generic and trade name(s)
p.000038: when approved) of the investigational product(s), all active ingredients, the investigational product (s )
p.000038: pharmacological class and its expected position within this class (e.g., advantages), the rationale for
p.000038: performing research with the investigational product(s), and the anticipated prophylactic, therapeutic, or diagnostic
p.000038: indication(s). Finally, the introductory statement should provide the general approach to be followed in evaluating the
p.000038: investigational product.
p.000038:
p.000038: 7.3.4 Physical, Chemical, and Pharmaceutical Properties and Formulation
p.000038:
p.000038: A description should be provided of the investigational product substance(s) (including the chemical and/or structural
p.000038: formula(e)), and a brief summary should be given of the relevant physical, chemical, and pharmaceutical properties.
p.000038:
p.000038: To permit appropriate safety measures to be taken in the course of the trial, a description of the formulation(s) to be
p.000038: used, including excipients, should be provided and justified if clinically relevant. Instructions for the storage and
p.000038: handling of the dosage form(s) should also be given.
p.000038:
p.000038: Any structural similarities to other known compounds should be mentioned.
p.000038: 7.3.5 Nonclinical Studies Introduction:
p.000038: The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic, and investigational product
p.000038: metabolism studies should be provided in summary form. This summary should address the methodology used,
p.000038: the results, and a discussion of the
p.000038:
p.000039: 39
p.000039:
p.000039: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000039:
p.000039: relevance of the findings to the investigated therapeutic and the possible unfavourable and unintended
p.000039: effects in humans.
p.000039: The information provided may include the following, as appropriate, if known/available:
p.000039: • Species tested
p.000039: • Number and sex of animals in each group
p.000039: • Unit dose (e.g., milligram/kilogram (mg/kg))
p.000039: • Dose interval
p.000039: • Route of administration
p.000039: • Duration of dosing
p.000039: • Information on systemic distribution
p.000039: • Duration of post-exposure follow-up
p.000039: • Results, including the following aspects:
p.000039: - Nature and frequency of pharmacological or toxic effects
p.000039: - Severity or intensity of pharmacological or toxic effects
p.000039: - Time to onset of effects
...
Health / Healthy People
Searching for indicator healthy volunteers:
(return to top)
p.000040: including information on pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy,
p.000040: and other pharmacological activities. Where possible, a summary of each completed clinical trial should be
p.000040: provided. Information should also be provided regarding results of any use of the investigational product(s) other
p.000040: than from in clinical trials, such as from experience during marketing.
p.000040: (a) Pharmacokinetics and Product Metabolism in Humans
p.000040: - A summary of information on the pharmacokinetics of the investigational product(s) should be
p.000040: presented, including the following, if available:
p.000040: - Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, distribution, and
p.000040: elimination).
p.000040: - Bioavailability of the investigational product (absolute, where possible, and/or relative) using a
p.000040: reference dosage form.
p.000040: - Population subgroups (e.g., gender, age, and impaired organ function).
p.000040: - Interactions (e.g., product-product interactions and effects of food).
p.000040: - Other pharmacokinetic data (e.g., results of population studies performed within clinical trial(s).
p.000040: (b) Safety and Efficacy
p.000040: A summary of information should be provided about the investigational product's/products'
p.000040: (including metabolites, where appropriate) safety, pharmacodynamics, efficacy, and dose response that were obtained
p.000040: from preceding trials in humans (healthy volunteers and/or patients). The implications of this information should be
p.000040: discussed. In cases where a number of clinical trials have been completed, the use of summaries of safety
p.000040: and efficacy across multiple trials by indications in subgroups may provide a clear presentation of the data. Tabular
p.000040: summaries of adverse drug reactions for all the clinical trials (including those for all the studied
p.000040: indications) would be useful. Important differences in adverse drug reaction patterns/incidences across indications
p.000040: or subgroups should be discussed.
p.000040: The IB should provide a description of the possible risks and adverse drug reactions to be anticipated on the basis
p.000040: of prior experiences with the product under investigation and with related products. A description should also
p.000040: be provided of the precautions or special monitoring to be done as part of the investigational use of the product(s).
p.000040: (c) Marketing Experience
p.000040: The IB should identify countries where the investigational product has been marketed or approved. Any significant
p.000040: information arising from the marketed use should be summarised (e.g., formulations, dosages, routes
p.000040: of administration, and adverse product reactions). The IB should also identify all the countries where the
p.000040: investigational product
p.000040:
p.000040:
p.000041: 41
p.000041:
p.000041: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000041:
p.000041: did not receive approval/registration for marketing or was withdrawn from
p.000041: marketing/registration.
p.000041:
...
Health / Mentally Disabled
Searching for indicator disability:
(return to top)
p.000005: 1.45 Protocol Amendment
p.000005: A written description of a change(s) to or formal clarification of a protocol.
p.000005: 1.46 Quality Assurance (QA)
p.000005: All those planned and systematic actions that are established to ensure that the trial is performed and the data are
p.000005: generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the
p.000005: applicable regulatory requirement(s).
p.000005: 1.47 Quality Control (QC)
p.000005: The operational techniques and activities undertaken within the quality assurance system to verify that the
p.000005: requirements for quality of the trial-related activities have been fulfilled.
p.000005: 1.48 Randomization
p.000005: The process of assigning trial subjects to treatment or control groups using an element of chance to determine the
p.000005: assignments in order to reduce bias.
p.000005: 1.49 Regulatory Authorities
p.000005: Bodies having the power to regulate. In the ICH GCP Guideline the expression Regulatory Authorities
p.000005: includes the authorities that review submitted clinical data and those that conduct inspections (see 1.29).
p.000005: These bodies are sometimes referred to as competent authorities.
p.000005:
p.000005:
p.000005:
p.000005:
p.000006: 6
p.000006:
p.000006: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000006:
p.000006: 1.50 Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)
p.000006: Any untoward medical occurrence that at any dose:
p.000006: - results in death,
p.000006: - is life-threatening,
p.000006: - requires inpatient hospitalization or prolongation of existing hospitalization,
p.000006: - results in persistent or significant disability/incapacity, or
p.000006: - is a congenital anomaly/birth defect
p.000006: (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited
p.000006: Reporting).
p.000006: 1.51 Source Data
p.000006: All information in original records and certified copies of original records of clinical findings, observations, or
p.000006: other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are
p.000006: contained in source documents (original records or certified copies).
p.000006: 1.52 Source Documents
p.000006: Original documents, data, and records (e.g., hospital records, clinical and office charts,
p.000006: laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records,
p.000006: recorded data from automated instruments, copies or transcriptions certified after verification as being
p.000006: accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files,
p.000006: and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical
p.000006: trial).
p.000006: 1.53 Sponsor
p.000006: An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or
p.000006: financing of a clinical trial.
p.000006: 1.54 Sponsor-Investigator
p.000006: An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate
p.000006: direction the investigational product is administered to, dispensed to, or used by a subject. The term does not
p.000006: include any person other than an individual (e.g., it does not include a corporation or an agency). The
...
Health / Mentally Incapacitated
Searching for indicator incapable:
(return to top)
p.000007: Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics
p.000007: for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for
p.000007: Expedited Reporting).
p.000007:
p.000007: 1.61 Vulnerable Subjects
p.000007: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether
p.000007: justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a
p.000007: hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure,
p.000007: such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees
p.000007: of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable
p.000007: subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons,
p.000007: patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and
p.000007: those incapable of giving consent.
p.000007: 1.62 Well-being (of the trial subjects)
p.000007: The physical and mental integrity of the subjects participating in a clinical trial.
p.000007: ADDENDUM
p.000007: 1.63 Certified Copy
p.000007: A copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated
p.000007: signature or by generation through a validated process) to have the same information, including data that describe the
p.000007: context, content, and structure, as the original.
p.000007: 1.64 Monitoring Plan
p.000007: A document that describes the strategy, methods, responsibilities, and requirements for monitoring
p.000007: the trial.
p.000007: 1.65 Validation of Computerized Systems
p.000007: A process of establishing and documenting that the specified requirements of a computerized system can be
p.000007: consistently fulfilled from design until decommissioning of the system or transition to a new system. The
p.000007: approach to validation should be based on a risk assessment that takes into consideration the intended use of the
p.000007: system and the potential of the system to affect human subject protection and reliability of trial results.
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000008: 8
p.000008:
p.000008: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000008:
p.000008:
p.000008: 2. THE PRINCIPLES OF ICH GCP
p.000008:
p.000008: 2.1 Clinical trials should be conducted in accordance with the ethical principles that have their
...
Health / Physically Disabled
Searching for indicator illness:
(return to top)
p.000012:
p.000012: ADDENDUM
p.000012: 4.2.5 The investigator is responsible for supervising any individual or party to whom the investigator
p.000012: delegates trial-related duties and functions conducted at the trial site.
p.000012:
p.000012: 4.2.6 If the investigator/institution retains the services of any individual or party to perform
p.000012: trial-related duties and functions, the investigator/institution should ensure this individual or party is qualified
p.000012: to perform those trial-related duties and functions and should implement procedures to ensure the
p.000012: integrity of the trial-related duties and functions performed and any data generated.
p.000012:
p.000013: 13
p.000013:
p.000013: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000013:
p.000013: 4.3 Medical Care of Trial Subjects
p.000013:
p.000013: 4.3.1 A qualified physician (or dentist, when appropriate), who is an investigator or a sub-
p.000013: investigator for the trial, should be responsible for all trial-related medical (or dental) decisions.
p.000013:
p.000013: 4.3.2 During and following a subject's participation in a trial, the investigator/institution should ensure that
p.000013: adequate medical care is provided to a subject for any adverse events, including clinically
p.000013: significant laboratory values, related to the trial. The investigator/institution should
p.000013: inform a subject when medical care is needed for intercurrent illness(es) of which the investigator
p.000013: becomes aware.
p.000013:
p.000013: 4.3.3 It is recommended that the investigator inform the subject's primary physician about the subject's
p.000013: participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician
p.000013: being informed.
p.000013:
p.000013: 4.3.4 Although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the
p.000013: investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights.
p.000013:
p.000013: 4.4 Communication with IRB/IEC
p.000013:
p.000013: 4.4.1 Before initiating a trial, the investigator/institution should have written and dated
p.000013: approval/favourable opinion from the IRB/IEC for the trial protocol, written informed consent form,
p.000013: consent form updates, subject recruitment procedures (e.g., advertisements), and any other written
p.000013: information to be provided to subjects.
p.000013:
p.000013: 4.4.2 As part of the investigator's/institution’s written application to the IRB/IEC, the
p.000013: investigator/institution should provide the IRB/IEC with a current copy of the Investigator's
p.000013: Brochure. If the Investigator's Brochure is updated during the trial, the investigator/institution should
p.000013: supply a copy of the updated Investigator’s Brochure to the IRB/IEC.
p.000013:
p.000013: 4.4.3 During the trial the investigator/institution should provide to the IRB/IEC all documents subject to review.
p.000013:
p.000013: 4.5 Compliance with Protocol
p.000013:
...
Health / Terminally Ill
Searching for indicator terminal:
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p.000019:
p.000019: 4.10.2 The investigator should promptly provide written reports to the sponsor, the IRB/IEC (see 3.3.8)
p.000019: and, where applicable, the institution on any changes significantly affecting the conduct of the trial, and/or
p.000019: increasing the risk to subjects.
p.000019:
p.000019: 4.11 Safety Reporting
p.000019:
p.000019: 4.11.1 All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that
p.000019: the protocol or other document (e.g., Investigator's Brochure) identifies as not needing immediate reporting.
p.000019: The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up
p.000019: reports should identify subjects by unique code numbers assigned to the trial subjects rather than by the subjects'
p.000019: names, personal identification numbers, and/or addresses. The investigator should also comply with the
p.000019: applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to
p.000019: the regulatory authority(ies) and the IRB/IEC.
p.000019:
p.000019: 4.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety
p.000019: evaluations should be reported to the sponsor according to the reporting requirements and within
p.000019: the time periods specified by the sponsor in the protocol.
p.000019:
p.000019: 4.11.3 For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any additional requested
p.000019: information (e.g., autopsy reports and terminal medical reports).
p.000019:
p.000019: 4.12 Premature Termination or Suspension of a Trial
p.000019: If the trial is prematurely terminated or suspended for any reason, the investigator/institution should
p.000019: promptly inform the trial subjects, should assure appropriate therapy and follow-up for the subjects, and, where
p.000019: required by the applicable regulatory requirement(s), should inform the regulatory authority(ies). In addition:
p.000019:
p.000019: 4.12.1 If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator
p.000019: should inform the institution where applicable, and the investigator/institution should promptly
p.000019: inform the sponsor and the IRB/IEC, and should provide the sponsor and the IRB/IEC a detailed written explanation of
p.000019: the termination or suspension.
p.000019:
p.000019: 4.12.2 If the sponsor terminates or suspends a trial (see 5.21), the investigator should promptly inform the
p.000019: institution where applicable and the investigator/institution should promptly inform the IRB/IEC and provide the
p.000019: IRB/IEC a detailed written explanation of the termination or suspension.
p.000019:
p.000019: 4.12.3 If the IRB/IEC terminates or suspends its approval/favourable opinion of a trial (see 3.1.2 and 3.3.9), the
p.000019: investigator should inform the institution where applicable and the investigator/institution should promptly
p.000019: notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension.
p.000019:
p.000019: 4.13 Final Report(s) by Investigator
p.000019: Upon completion of the trial, the investigator, where applicable, should inform the institution; the
...
Social / Access to Social Goods
Searching for indicator access:
(return to top)
p.000014: 14
p.000014: 4.6 Investigational Product(s)
p.000015: 15
p.000015: 4.7 Randomization Procedures and Unblinding
p.000015: 15
p.000015: 4.8 Informed Consent of Trial Subjects
p.000016: 16
p.000016: 4.9 Records and Reports
p.000019: 19
p.000019: 4.10 Progress Reports
p.000019: 19
p.000019: 4.11 Safety Reporting
p.000020: 20
p.000020: 4.12 Premature Termination or Suspension of a Trial
p.000020: 20
p.000020: 4.13 Final Report(s) by Investigator
p.000020: 20
p.000020: 5. SPONSOR
p.000021: 21
p.000021: 5.0 Quality Management
p.000021: 21
p.000021: 5.1 Quality Assurance and Quality Control
p.000022: 22
p.000022: 5.2 Contract Research Organization (CRO)
p.000022: 22
p.000022: 5.3 Medical Expertise
p.000023: 23
p.000023: i
p.000023:
p.000023: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000023: 5.4 Trial Design
p.000023: 23
p.000023: 5.5 Trial Management, Data Handling, and Record Keeping 23
p.000023: 5.6 Investigator Selection
p.000025: 25
p.000025: 5.7 Allocation of Responsibilities
p.000025: 25
p.000025: 5.8 Compensation to Subjects and Investigators
p.000025: 25
p.000025: 5.9 Financing
p.000026: 26
p.000026: 5.10 Notification/Submission to Regulatory Authority(ies)
p.000026: 26
p.000026: 5.11 Confirmation of Review by IRB/IEC
p.000026: 26
p.000026: 5.12 Information on Investigational Product(s)
p.000026: 26
p.000026: 5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s) 27
p.000026: 5.14 Supplying and Handling Investigational Product(s)
p.000027: 27
p.000027: 5.15 Record Access
p.000028: 28
p.000028: 5.16 Safety Information
p.000028: 28
p.000028: 5.17 Adverse Drug Reaction Reporting
p.000028: 28
p.000028: 5.18 Monitoring
p.000029: 29
p.000029: 5.18.1 Purpose
p.000029: 29
p.000029: 5.18.2 Selection and Qualifications of Monitors 29
p.000029: 5.18.3 Extent and Nature of Monitoring
p.000029: 29
p.000029: 5.18.5 Monitoring Procedures
p.000031: 31
p.000031: 5.18.6 Monitoring Report
p.000032: 32
p.000032: 5.18.7 Monitoring Plan
p.000032: 32
p.000032: 5.19 Audit
p.000032: 32
p.000032: 5.19.1 Purpose
p.000032: 32
p.000032: 5.19.2 Selection and Qualification of Auditors 32
p.000032: 5.19.3 Auditing Procedures
p.000033: 33
p.000033: 5.20 Noncompliance
p.000033: 33
p.000033: 5.21 Premature Termination or Suspension of a Trial
p.000033: 33
p.000033: 5.22 Clinical Trial/Study Reports
p.000033: 33
p.000033: 5.23 Multicentre Trials
p.000034: 34
p.000034: 6. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S) 34
p.000034: 6.1 General Information
p.000034: 34
p.000034: 6.2 Background Information
p.000035: 35
p.000035: 6.3 Trial Objectives and Purpose
p.000035: 35
p.000035: 6.4 Trial Design
p.000035: 35
p.000035: 6.5 Selection and Withdrawal of Subjects
p.000036: 36
p.000036: 6.6 Treatment of Subjects
p.000036: 36
p.000036: 6.7 Assessment of Efficacy
p.000036: 36
p.000036: ii
p.000036:
p.000036: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000036: 6.8 Assessment of Safety
p.000036: 36
p.000036: 6.9 Statistics
p.000037: 37
p.000037: 6.10 Direct Access to Source Data/Documents
p.000037: 37
p.000037: 6.11 Quality Control and Quality Assurance
p.000037: 37
p.000037: 6.12 Ethics
p.000037: 37
p.000037: 6.13 Data Handling and Record Keeping
p.000037: 37
p.000037: 6.14 Financing and Insurance
p.000037: 37
p.000037: 6.15 Publication Policy
p.000037: 37
p.000037: 6.16 Supplements
p.000037: 37
p.000037: 7. INVESTIGATOR’S BROCHURE
p.000038: 38
p.000038: 7.1 Introduction
p.000038: 38
p.000038: 7.2 General Considerations
p.000038: 38
p.000038: 7.2.1 Title Page
p.000038: 38
p.000038: 7.2.2 Confidentiality Statement
p.000039: 39
p.000039: 7.3 Contents of the Investigator’s Brochure
p.000039: 39
p.000039: 7.3.1 Table of Contents
p.000039: 39
p.000039: 7.3.2 Summary
p.000039: 39
p.000039: 7.3.3 Introduction
p.000039: 39
p.000039: 7.3.4 Physical, Chemical, and Pharmaceutical Properties and Formulation 39
p.000039: 7.3.5 Nonclinical Studies
p.000039: 39
p.000039: 7.3.6 Effects in Humans
p.000041: 41
p.000041: 7.3.7 Summary of Data and Guidance for the Investigator 42
p.000041: 7.4 APPENDIX 1:
p.000043: 43
p.000043: 7.5 APPENDIX 2:
p.000044: 44
p.000044: 8. ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL 45
p.000044: 8.1 Introduction
p.000045: 45
p.000045: 8.2 Before the Clinical Phase of the Trial Commences
p.000046: 46
p.000046: 8.3 During the Clinical Conduct of the Trial
p.000053: 53
p.000053: 8.4 After Completion or Termination of the Trial
p.000059: 59
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059: iii
p.000059:
p.000059:
p.000059:
...
p.000002: 1.14 Comparator (Product)
p.000002: An investigational or marketed product (i.e., active control), or placebo, used as a reference in a clinical trial.
p.000002: 1.15 Compliance (in relation to trials)
p.000002: Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements, and the applicable
p.000002: regulatory requirements.
p.000002: 1.16 Confidentiality
p.000002: Prevention of disclosure, to other than authorized individuals, of a sponsor's proprietary information or of
p.000002: a subject's identity.
p.000002: 1.17 Contract
p.000002: A written, dated, and signed agreement between two or more involved parties that sets out any arrangements on
p.000002: delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol
p.000002: may serve as the basis of a contract.
p.000002: 1.18 Coordinating Committee
p.000002: A committee that a sponsor may organize to coordinate the conduct of a multicentre trial.
p.000002: 1.19 Coordinating Investigator
p.000002: An investigator assigned the responsibility for the coordination of investigators at different centres
p.000002: participating in a multicentre trial.
p.000002:
p.000002:
p.000002:
p.000002:
p.000003: 3
p.000003:
p.000003: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000003:
p.000003: 1.20 Contract Research Organization (CRO)
p.000003: A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or
p.000003: more of a sponsor's trial-related duties and functions.
p.000003: 1.21 Direct Access
p.000003: Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a
p.000003: clinical trial. Any party (e.g., domestic and foreign regulatory authorities, sponsor's monitors and auditors)
p.000003: with direct access should take all reasonable precautions within the constraints of the applicable regulatory
p.000003: requirement(s) to maintain the confidentiality of subjects' identities and sponsor’s proprietary information.
p.000003: 1.22 Documentation
p.000003: All records, in any form (including, but not limited to, written, electronic, magnetic, and optical records, and scans,
p.000003: x-rays, and electrocardiograms) that describe or record the methods, conduct, and/or results of a trial, the factors
p.000003: affecting a trial, and the actions taken.
p.000003: 1.23 Essential Documents
p.000003: Documents which individually and collectively permit evaluation of the conduct of a study and the quality of the data
p.000003: produced (see 8. Essential Documents for the Conduct of a Clinical Trial).
p.000003: 1.24 Good Clinical Practice (GCP)
p.000003: A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and reporting of clinical
p.000003: trials that provides assurance that the data and reported results are credible and accurate, and that the rights,
p.000003: integrity, and confidentiality of trial subjects are protected.
p.000003: 1.25 Independent Data-Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee,
p.000003: Data Monitoring Committee)
p.000003: An independent data-monitoring committee that may be established by the sponsor to assess at intervals the progress of
p.000003: a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to
p.000003: continue, modify, or stop a trial.
p.000003: 1.26 Impartial Witness
p.000003: A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who
...
p.000016: (a) That the trial involves research.
p.000016: (b) The purpose of the trial.
p.000016: (c) The trial treatment(s) and the probability for random assignment to each treatment.
p.000016: (d) The trial procedures to be followed, including all invasive procedures.
p.000016: (e) The subject's responsibilities.
p.000016: (f) Those aspects of the trial that are experimental.
p.000016: (g) The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo,
p.000016: fetus, or nursing infant.
p.000016: (h) The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be
p.000016: made aware of this.
p.000016: (i) The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their
p.000016: important potential benefits and risks.
p.000016: (j) The compensation and/or treatment available to the subject in the event of trial- related injury.
p.000016: (k) The anticipated prorated payment, if any, to the subject for participating in the trial.
p.000016: (l) The anticipated expenses, if any, to the subject for participating in the trial.
p.000016: (m) That the subject's participation in the trial is voluntary and that the subject may refuse to
p.000016: participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is
p.000016: otherwise entitled.
p.000016: (n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted
p.000016: direct access to the subject's original medical records for verification of clinical trial procedures and/or data,
p.000016: without violating the confidentiality of the subject, to the extent permitted by the applicable laws and
p.000016: regulations and that, by signing a written informed consent form, the subject or the subject's legally
p.000016: acceptable representative is authorizing such access.
p.000016: (o) That records identifying the subject will be kept confidential and, to the extent permitted by the
p.000016: applicable laws and/or regulations, will not be made publicly available. If the results of the trial are
p.000016: published, the subject’s identity will remain confidential.
p.000016: (p) That the subject or the subject's legally acceptable representative will be informed in a timely manner if
p.000016: information becomes available that may be relevant to the subject's willingness to continue participation in
p.000016: the trial.
p.000016:
p.000017: 17
p.000017:
p.000017: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000017:
p.000017: (q) The person(s) to contact for further information regarding the trial and the rights of trial subjects, and whom to
p.000017: contact in the event of trial-related injury.
p.000017: (r) The foreseeable circumstances and/or reasons under which the subject's participation in the trial may be
p.000017: terminated.
p.000017: (s) The expected duration of the subject's participation in the trial.
p.000017: (t) The approximate number of subjects involved in the trial.
p.000017:
p.000017: 4.8.11 Prior to participation in the trial, the subject or the subject's legally acceptable
p.000017: representative should receive a copy of the signed and dated written informed consent form and any other
p.000017: written information provided to the subjects. During a subject’s participation in the trial, the subject
p.000017: or the subject’s legally acceptable representative should receive a copy of the signed and dated consent form
p.000017: updates and a copy of any amendments to the written information provided to subjects.
...
p.000018: should have written procedures to assure that changes or corrections in CRFs made by sponsor's designated
p.000018: representatives are documented, are necessary, and are endorsed by the investigator. The investigator should retain
p.000018: records of the changes and corrections.
p.000018:
p.000018: 4.9.4 The investigator/institution should maintain the trial documents as specified in Essential Documents for the
p.000018: Conduct of a Clinical Trial (see 8.) and as required by the applicable regulatory requirement(s). The
p.000018: investigator/institution should take measures to prevent accidental or premature destruction of these documents.
p.000018:
p.000018: 4.9.5 Essential documents should be retained until at least 2-years after the last approval of a marketing
p.000018: application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or
p.000018: at least 2-years have elapsed since the formal discontinuation of clinical development of the investigational product.
p.000018: These documents should be retained for a longer period however if required by the applicable regulatory requirements or
p.000018: by an agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to
p.000018: when these documents no longer need to be retained (see 5.5.12).
p.000018:
p.000018: 4.9.6 The financial aspects of the trial should be documented in an agreement between the sponsor and
p.000018: the investigator/institution.
p.000018:
p.000018: 4.9.7 Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the
p.000018: investigator/institution should make available for direct access all requested trial-related records.
p.000018:
p.000018: 4.10 Progress Reports
p.000018:
p.000018: 4.10.1 The investigator should submit written summaries of the trial status to the IRB/IEC annually, or
p.000018: more frequently, if requested by the IRB/IEC.
p.000018:
p.000019: 19
p.000019:
p.000019: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000019:
p.000019: 4.10.2 The investigator should promptly provide written reports to the sponsor, the IRB/IEC (see 3.3.8)
p.000019: and, where applicable, the institution on any changes significantly affecting the conduct of the trial, and/or
p.000019: increasing the risk to subjects.
p.000019:
p.000019: 4.11 Safety Reporting
p.000019:
p.000019: 4.11.1 All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that
p.000019: the protocol or other document (e.g., Investigator's Brochure) identifies as not needing immediate reporting.
p.000019: The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up
p.000019: reports should identify subjects by unique code numbers assigned to the trial subjects rather than by the subjects'
p.000019: names, personal identification numbers, and/or addresses. The investigator should also comply with the
p.000019: applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to
p.000019: the regulatory authority(ies) and the IRB/IEC.
p.000019:
p.000019: 4.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety
...
p.000021: determine if action is needed.
p.000021: 5.0.5 Risk Communication
p.000021: The sponsor should document quality management activities. The sponsor should communicate quality management
p.000021: activities to those who are involved in or affected by such activities, to facilitate risk review and continual
p.000021: improvement during clinical trial execution.
p.000021: 5.0.6 Risk Review
p.000021: The sponsor should periodically review risk control measures to ascertain whether the implemented quality management
p.000021: activities remain effective and relevant, taking into account emerging knowledge and experience.
p.000021: 5.0.7 Risk Reporting
p.000021: The sponsor should describe the quality management approach implemented in the trial and summarize important
p.000021: deviations from the predefined quality tolerance limits and remedial actions taken in the clinical study
p.000021: report (ICH E3, Section 9.6 Data Quality Assurance).
p.000021: 5.1 Quality Assurance and Quality Control
p.000021:
p.000021: 5.1.1 The sponsor is responsible for implementing and maintaining quality assurance and quality control
p.000021: systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and
p.000021: reported in compliance with the protocol, GCP, and the applicable regulatory requirement(s).
p.000021:
p.000021: 5.1.2 The sponsor is responsible for securing agreement from all involved parties to ensure direct
p.000021: access (see 1.21) to all trial related sites, source data/documents , and reports for the purpose of monitoring and
p.000021: auditing by the sponsor, and inspection by domestic and foreign regulatory authorities.
p.000021:
p.000021: 5.1.3 Quality control should be applied to each stage of data handling to ensure that all data are reliable and have
p.000021: been processed correctly.
p.000021:
p.000021: 5.1.4 Agreements, made by the sponsor with the investigator/institution and any other parties involved with the
p.000021: clinical trial, should be in writing, as part of the protocol or in a separate agreement.
p.000021:
p.000021: 5.2 Contract Research Organization (CRO)
p.000021:
p.000021: 5.2.1 A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO, but the
p.000021: ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. The CRO
p.000021: should implement quality assurance and quality control.
p.000021:
p.000021: 5.2.2 Any trial-related duty and function that is transferred to and assumed by a CRO should be specified in
p.000021: writing.
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000021:
p.000022: 22
p.000022:
p.000022: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000022:
p.000022: ADDENDUM
p.000022: The sponsor should ensure oversight of any trial-related duties and functions carried out on its behalf, including
p.000022: trial-related duties and functions that are subcontracted to another party by the sponsor’s contracted CRO(s).
p.000022: 5.2.3 Any trial-related duties and functions not specifically transferred to and assumed by a CRO are
p.000022: retained by the sponsor.
p.000022:
...
p.000022: (a) Ensure and document that the electronic data processing system(s) conforms to the sponsor’s established
p.000022: requirements for completeness, accuracy, reliability, and consistent intended performance (i.e., validation).
p.000022: ADDENDUM
p.000022: The sponsor should base their approach to validation of such systems on a risk assessment that takes
p.000022: into consideration the intended use of the system and the potential of the system to affect human
p.000022: subject protection and reliability of trial results.
p.000022:
p.000022:
p.000023: 23
p.000023:
p.000023: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000023:
p.000023: (b) Maintains SOPs for using these systems.
p.000023: ADDENDUM
p.000023: The SOPs should cover system setup, installation, and use. The SOPs should describe system validation and
p.000023: functionality testing, data collection and handling, system maintenance, system security measures,
p.000023: change control, data backup, recovery, contingency planning, and decommissioning. The responsibilities of
p.000023: the sponsor, investigator, and other parties with respect to the use of these computerized systems should be clear, and
p.000023: the users should be provided with training in their use.
p.000023: (c) Ensure that the systems are designed to permit data changes in such a way that the data changes are documented
p.000023: and that there is no deletion of entered data (i.e., maintain an audit trail, data trail, edit trail).
p.000023: (d) Maintain a security system that prevents unauthorized access to the data.
p.000023: (e) Maintain a list of the individuals who are authorized to make data changes (see 4.1.5 and 4.9.3).
p.000023: (f) Maintain adequate backup of the data.
p.000023: (g) Safeguard the blinding, if any (e.g., maintain the blinding during data entry and processing).
p.000023: ADDENDUM
p.000023: (h) Ensure the integrity of the data including any data that describe the context, content, and structure. This
p.000023: is particularly important when making changes to the computerized systems, such as software upgrades or
p.000023: migration of data.
p.000023: 5.5.4 If data are transformed during processing, it should always be possible to compare the original data and
p.000023: observations with the processed data.
p.000023:
p.000023: 5.5.5 The sponsor should use an unambiguous subject identification code (see 1.58) that allows identification of all
p.000023: the data reported for each subject.
p.000023:
p.000023: 5.5.6 The sponsor, or other owners of the data, should retain all of the sponsor-specific essential
p.000023: documents pertaining to the trial (see 8. Essential Documents for the Conduct of a Clinical Trial).
p.000023:
p.000023: 5.5.7 The sponsor should retain all sponsor-specific essential documents in conformance with the applicable
p.000023: regulatory requirement(s) of the country(ies) where the product is approved, and/or where the sponsor
p.000023: intends to apply for approval(s).
p.000023:
p.000023: 5.5.8 If the sponsor discontinues the clinical development of an investigational product (i.e., for any or all
p.000023: indications, routes of administration, or dosage forms), the sponsor should maintain all sponsor-specific essential
p.000023: documents for at least 2-years after formal discontinuation or in conformance with the applicable regulatory
p.000023: requirement(s).
p.000023:
...
p.000026: sponsor (or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory
p.000026: requirement(s)).
p.000026:
p.000026: 5.14.4 The sponsor should:
p.000026: (a) Ensure timely delivery of investigational product(s) to the investigator(s).
p.000026: (b) Maintain records that document shipment, receipt, disposition, return, and destruction of the
p.000026: investigational product(s) (see 8. Essential Documents for the Conduct of a Clinical Trial).
p.000026:
p.000026:
p.000026:
p.000027: 27
p.000027:
p.000027: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000027:
p.000027: (c) Maintain a system for retrieving investigational products and documenting this retrieval (e.g., for
p.000027: deficient product recall, reclaim after trial completion, expired product reclaim).
p.000027: (d) Maintain a system for the disposition of unused investigational product(s) and for the documentation of this
p.000027: disposition.
p.000027:
p.000027: 5.14.5 The sponsor should:
p.000027: (a) Take steps to ensure that the investigational product(s) are stable over the period of use.
p.000027: (b) Maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm
p.000027: specifications, should this become necessary, and maintain records of batch sample analyses and
p.000027: characteristics. To the extent stability permits, samples should be retained either until the analyses of
p.000027: the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the
p.000027: longer retention period.
p.000027:
p.000027: 5.15 Record Access
p.000027:
p.000027: 5.15.1 The sponsor should ensure that it is specified in the protocol or other written agreement that the
p.000027: investigator(s)/institution(s) provide direct access to source data/documents for trial-related monitoring, audits,
p.000027: IRB/IEC review, and regulatory inspection.
p.000027:
p.000027: 5.15.2 The sponsor should verify that each subject has consented, in writing, to direct access to his/her original
p.000027: medical records for trial-related monitoring, audit, IRB/IEC review, and regulatory inspection.
p.000027:
p.000027: 5.16 Safety Information
p.000027:
p.000027: 5.16.1 The sponsor is responsible for the ongoing safety evaluation of the investigational product(s).
p.000027:
p.000027: 5.16.2 The sponsor should promptly notify all concerned investigator(s)/institution(s) and the regulatory
p.000027: authority(ies) of findings that could affect adversely the safety of subjects, impact the conduct of the
p.000027: trial, or alter the IRB/IEC's approval/favourable opinion to continue the trial.
p.000027:
p.000027: 5.17 Adverse Drug Reaction Reporting
p.000027:
p.000027: 5.17.1 The sponsor should expedite the reporting to all concerned investigator(s)/institutions(s), to the
p.000027: IRB(s)/IEC(s), where required, and to the regulatory authority(ies) of all adverse drug reactions (ADRs) that are both
p.000027: serious and unexpected.
p.000027:
p.000027: 5.17.2 Such expedited reports should comply with the applicable regulatory requirement(s) and with the ICH Guideline
p.000027: for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.
p.000027:
p.000027: 5.17.3 The sponsor should submit to the regulatory authority(ies) all safety updates and periodic reports, as required
p.000027: by applicable regulatory requirement(s).
p.000027:
p.000027:
p.000027:
p.000028: 28
p.000028:
p.000028: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
...
p.000031: quality control functions, should be to evaluate trial conduct and compliance with the protocol,
p.000031: SOPs, GCP, and the applicable regulatory requirements.
p.000031:
p.000031: 5.19.2 Selection and Qualification of Auditors
p.000031: (a) The sponsor should appoint individuals, who are independent of the clinical trials/systems,
p.000031: to conduct audits.
p.000031: (b) The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly.
p.000031: An auditor’s qualifications should be documented.
p.000031:
p.000031:
p.000031:
p.000031:
p.000031:
p.000032: 32
p.000032:
p.000032: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000032:
p.000032:
p.000032: 5.19.3 Auditing Procedures
p.000032: (a) The sponsor should ensure that the auditing of clinical trials/systems is conducted in accordance with the
p.000032: sponsor's written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit
p.000032: reports.
p.000032: (b) The sponsor's audit plan and procedures for a trial audit should be guided by the importance of
p.000032: the trial to submissions to regulatory authorities, the number of subjects in the trial, the type and
p.000032: complexity of the trial, the level of risks to the trial subjects, and any identified problem(s).
p.000032: (c) The observations and findings of the auditor(s) should be documented.
p.000032: (d) To preserve the independence and value of the audit function, the regulatory authority(ies) should not
p.000032: routinely request the audit reports. Regulatory authority(ies) may seek access to an audit report on a case by case
p.000032: basis when evidence of serious GCP non-compliance exists, or in the course of legal proceedings.
p.000032: (e) When required by applicable law or regulation, the sponsor should provide an audit certificate.
p.000032:
p.000032: 5.20 Noncompliance
p.000032:
p.000032: 5.20.1 Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s)
p.000032: by an investigator/institution, or by member(s) of the sponsor's staff should lead to prompt action by the
p.000032: sponsor to secure compliance.
p.000032: ADDENDUM
p.000032: If noncompliance that significantly affects or has the potential to significantly affect human subject
p.000032: protection or reliability of trial results is discovered, the sponsor should perform a root cause analysis and
p.000032: implement appropriate corrective and preventive actions.
p.000032: 5.20.2 If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an
p.000032: investigator/institution, the sponsor should terminate the investiga- tor's/institution’s participation in the
p.000032: trial. When an investigator's/institution’s parti- cipation is terminated because of noncompliance, the sponsor
p.000032: should notify promptly the regulatory authority(ies).
p.000032:
p.000032: 5.21 Premature Termination or Suspension of a Trial
p.000032: If a trial is prematurely terminated or suspended, the sponsor should promptly inform the
p.000032: investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the reason(s) for
...
p.000035:
p.000035: 6.8.1 Specification of safety parameters.
p.000035:
p.000035: 6.8.2 The methods and timing for assessing, recording, and analysing safety parameters.
p.000035:
p.000035: 6.8.3 Procedures for eliciting reports of and for recording and reporting adverse event and intercurrent
p.000035: illnesses.
p.000035:
p.000035: 6.8.4 The type and duration of the follow-up of subjects after adverse events.
p.000035:
p.000035:
p.000036: 36
p.000036:
p.000036: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000036:
p.000036: 6.9 Statistics
p.000036: 6.9.1 A description of the statistical methods to be employed, including timing of any planned interim
p.000036: analysis(ses).
p.000036:
p.000036: 6.9.2 The number of subjects planned to be enrolled. In multicentre trials, the numbers of enrolled
p.000036: subjects projected for each trial site should be specified. Reason for choice of sample size, including reflections
p.000036: on (or calculations of) the power of the trial and clinical justification.
p.000036:
p.000036: 6.9.3 The level of significance to be used.
p.000036:
p.000036: 6.9.4 Criteria for the termination of the trial.
p.000036:
p.000036: 6.9.5 Procedure for accounting for missing, unused, and spurious data.
p.000036:
p.000036: 6.9.6 Procedures for reporting any deviation(s) from the original statistical plan (any
p.000036: deviation(s) from the original statistical plan should be described and justified in protocol and/or in the final
p.000036: report, as appropriate).
p.000036:
p.000036: 6.9.7 The selection of subjects to be included in the analyses (e.g., all randomized subjects, all dosed subjects,
p.000036: all eligible subjects, evaluable subjects).
p.000036:
p.000036: 6.10 Direct Access to Source Data/Documents
p.000036: The sponsor should ensure that it is specified in the protocol or other written agreement that the
p.000036: investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, and regulatory
p.000036: inspection(s), providing direct access to source data/documents.
p.000036:
p.000036: 6.11 Quality Control and Quality Assurance
p.000036:
p.000036: 6.12 Ethics
p.000036: Description of ethical considerations relating to the trial.
p.000036:
p.000036: 6.13 Data Handling and Record Keeping
p.000036:
p.000036: 6.14 Financing and Insurance
p.000036: Financing and insurance if not addressed in a separate agreement.
p.000036:
p.000036: 6.15 Publication Policy
p.000036: Publication policy, if not addressed in a separate agreement.
p.000036:
p.000036: 6.16 Supplements
p.000036: (NOTE: Since the protocol and the clinical trial/study report are closely related, further relevant information can
p.000036: be found in the ICH Guideline for Structure and Content of Clinical Study Reports.)
p.000036:
p.000036:
p.000036:
p.000036:
p.000036:
p.000036:
p.000037: 37
p.000037:
p.000037: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000037:
p.000037: 7. INVESTIGATOR’S BROCHURE
p.000037: 7.1 Introduction
p.000037: The Investigator's Brochure (IB) is a compilation of the clinical and nonclinical data on the
p.000037: investigational product(s) that are relevant to the study of the product(s) in human subjects. Its purpose is to
p.000037: provide the investigators and others involved in the trial with the information to facilitate their understanding of
p.000037: the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose
p.000037: frequency/interval, methods of administration: and safety monitoring procedures. The IB also provides insight to
p.000037: support the clinical management of the study subjects during the course of the clinical trial. The information should
...
p.000044: investigator/institution or sponsor files, or both. It is acceptable to combine some of the documents, provided the
p.000044: individual elements are readily identifiable.
p.000044: Trial master files should be established at the beginning of the trial, both at the investigator/institution’s site and
p.000044: at the sponsor's office. A final close-out of a trial can only be done when the monitor has reviewed both
p.000044: investigator/institution and sponsor files and confirmed that all necessary documents are in the appropriate
p.000044: files.
p.000044: Any or all of the documents addressed in this guideline may be subject to, and should be available
p.000044: for, audit by the sponsor’s auditor and inspection by the regulatory authority(ies).
p.000044: ADDENDUM
p.000044: The sponsor and investigator/institution should maintain a record of the location(s) of their respective
p.000044: essential documents including source documents. The storage system used during the trial and for archiving
p.000044: (irrespective of the type of media used) should provide for document identification, version history, search,
p.000044: and retrieval.
p.000044: Essential documents for the trial should be supplemented or may be reduced where justified (in advance
p.000044: of trial initiation) based on the importance and relevance of the specific documents to the trial.
p.000044:
p.000044:
p.000044:
p.000045: 45
p.000045:
p.000045: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000045:
p.000045: The sponsor should ensure that the investigator has control of and continuous access to the CRF data reported to the
p.000045: sponsor. The sponsor should not have exclusive control of those data.
p.000045: When a copy is used to replace an original document (e.g., source documents, CRF), the copy should fulfill the
p.000045: requirements for certified copies.
p.000045: The investigator/institution should have control of all essential documents and records generated by the
p.000045: investigator/institution before, during, and after the trial.
p.000045:
p.000045: 8.2 Before the Clinical Phase of the Trial Commences
p.000045: During this planning stage the following documents should be generated and should be on file before the trial formally
p.000045: starts
p.000045:
p.000045:
p.000045: Title of Document
p.000045: Purpose
p.000045: Located in Files of
p.000045:
p.000045:
p.000045:
p.000045: 8.2.1
p.000045:
p.000045:
p.000045: 8.2.2
p.000045:
p.000045:
p.000045: 8.2.3
p.000045:
p.000045:
p.000045: INVESTIGATOR’S BROCHURE
p.000045:
p.000045:
p.000045: SIGNED PROTOCOL AND AMENDMENTS, IF ANY, AND SAMPLE CASE REPORT FORM (CRF)
p.000045:
p.000045: INFORMATION GIVEN TO TRIAL SUBJECT
p.000045: - INFORMED CONSENT FORM
p.000045: (including all applicable translations)
p.000045: - ANY OTHER WRITTEN INFORMATION
p.000045:
p.000045:
p.000045: To document that relevant and current scientific information about the investigational product has been
p.000045: provided to the investigator
p.000045:
p.000045: To document investigator and sponsor agreement to the protocol/amendment(s) and CRF
p.000045:
p.000045:
p.000045:
p.000045: To document the informed consent
p.000045:
p.000045: To document that subjects will be given appropriate written information (content and
...
p.000054:
p.000054:
p.000054:
p.000054:
p.000054:
p.000054: X
p.000054:
p.000054:
p.000054: X
p.000054:
p.000054:
p.000054: X
p.000054:
p.000054:
p.000054:
p.000054:
p.000054:
p.000054:
p.000054:
p.000055: 55
p.000055:
p.000055: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000055:
p.000055:
p.000055: Title of Document
p.000055: Purpose
p.000055: Located in Files of
p.000055:
p.000055:
p.000055:
p.000055: 8.3.11
p.000055:
p.000055:
p.000055: RELEVANT COMMUNICATIONS OTHER THAN SITE VISITS
p.000055: - letters
p.000055: - meeting notes
p.000055: - notes of telephone calls
p.000055:
p.000055:
p.000055: To document any agreements or significant discussions regarding trial administration, protocol
p.000055: violations, trial conduct, adverse event (AE) reporting
p.000055: Investigator/ Institution
p.000055: X
p.000055: Sponsor
p.000055:
p.000055: X
p.000055:
p.000055:
p.000055: 8.3.12
p.000055:
p.000055:
p.000055:
p.000055: 8.3.13
p.000055:
p.000055:
p.000055:
p.000055: 8.3.14
p.000055:
p.000055:
p.000055: 8.3.15
p.000055:
p.000055: 8.3.16
p.000055: SIGNED INFORMED CONSENT FORMS
p.000055:
p.000055:
p.000055:
p.000055: SOURCE DOCUMENTS
p.000055:
p.000055:
p.000055:
p.000055: SIGNED, DATED AND COMPLETED CASE REPORT FORMS (CRF)
p.000055:
p.000055: DOCUMENTATION OF CRF CORRECTIONS
p.000055:
p.000055: NOTIFICATION BY ORIGINATING INVESTIGATOR TO SPONSOR OF SERIOUS ADVERSE EVENTS AND RELATED REPORTS
p.000055: To document that consent is obtained in accordance with GCP and protocol and dated prior to
p.000055: participation of each subject in trial. Also to document direct access permission (see 8.2.3)
p.000055:
p.000055: To document the existence of the subject and substantiate integrity of trial data collected. To include
p.000055: original documents related to the trial, to medical treatment, and history of subject
p.000055:
p.000055: To document that the investigator or authorised member of the investigator’s staff confirms the
p.000055: observations recorded
p.000055:
p.000055: To document all changes/additions or corrections made to CRF after initial data were recorded
p.000055:
p.000055: Notification by originating investigator to sponsor of serious adverse events and related reports in accordance
p.000055: with 4.11
p.000055: X
p.000055:
p.000055:
p.000055:
p.000055: X
p.000055:
p.000055:
p.000055:
p.000055: X
p.000055: (copy)
p.000055:
p.000055: X
p.000055: (copy) X
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055: X
p.000055: (original)
p.000055:
p.000055: X
p.000055: (original) X
p.000055:
p.000055:
p.000056: 56
p.000056:
p.000056: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000056:
p.000056:
p.000056: Title of Document
p.000056: Purpose
p.000056: Located in Files of
p.000056:
p.000056:
p.000056:
p.000056: 8.3.17
p.000056:
p.000056:
p.000056:
p.000056:
p.000056:
p.000056: 8.3.18
p.000056:
p.000056:
p.000056: 8.3.19
p.000056:
p.000056:
p.000056: 8.3.20
p.000056:
p.000056:
p.000056: 8.3.21
p.000056:
p.000056:
p.000056: NOTIFICATION BY SPONSOR AND/OR INVESTIGATOR, WHERE APPLICABLE, TO REGULATORY AUTHORITY(IES) AND IRB(S)/IEC(S) OF
p.000056: UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS AND OF OTHER SAFETY INFORMATION
p.000056:
...
Social / Age
Searching for indicator age:
(return to top)
p.000039: described under the following headings where appropriate:
p.000039:
p.000039:
p.000040: 40
p.000040:
p.000040: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000040:
p.000040: - Single dose
p.000040: - Repeated dose
p.000040: - Carcinogenicity
p.000040: - Special studies (e.g., irritancy and sensitisation)
p.000040: - Reproductive toxicity
p.000040: - Genotoxicity (mutagenicity)
p.000040: 7.3.6 Effects in Humans Introduction:
p.000040: A thorough discussion of the known effects of the investigational product(s) in humans should be provided,
p.000040: including information on pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy,
p.000040: and other pharmacological activities. Where possible, a summary of each completed clinical trial should be
p.000040: provided. Information should also be provided regarding results of any use of the investigational product(s) other
p.000040: than from in clinical trials, such as from experience during marketing.
p.000040: (a) Pharmacokinetics and Product Metabolism in Humans
p.000040: - A summary of information on the pharmacokinetics of the investigational product(s) should be
p.000040: presented, including the following, if available:
p.000040: - Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, distribution, and
p.000040: elimination).
p.000040: - Bioavailability of the investigational product (absolute, where possible, and/or relative) using a
p.000040: reference dosage form.
p.000040: - Population subgroups (e.g., gender, age, and impaired organ function).
p.000040: - Interactions (e.g., product-product interactions and effects of food).
p.000040: - Other pharmacokinetic data (e.g., results of population studies performed within clinical trial(s).
p.000040: (b) Safety and Efficacy
p.000040: A summary of information should be provided about the investigational product's/products'
p.000040: (including metabolites, where appropriate) safety, pharmacodynamics, efficacy, and dose response that were obtained
p.000040: from preceding trials in humans (healthy volunteers and/or patients). The implications of this information should be
p.000040: discussed. In cases where a number of clinical trials have been completed, the use of summaries of safety
p.000040: and efficacy across multiple trials by indications in subgroups may provide a clear presentation of the data. Tabular
p.000040: summaries of adverse drug reactions for all the clinical trials (including those for all the studied
p.000040: indications) would be useful. Important differences in adverse drug reaction patterns/incidences across indications
p.000040: or subgroups should be discussed.
p.000040: The IB should provide a description of the possible risks and adverse drug reactions to be anticipated on the basis
p.000040: of prior experiences with the product under investigation and with related products. A description should also
p.000040: be provided of the precautions or special monitoring to be done as part of the investigational use of the product(s).
p.000040: (c) Marketing Experience
...
Social / Ethnicity
Searching for indicator ethnic:
(return to top)
p.000007: 1.59 Trial Site
p.000007: The location(s) where trial-related activities are actually conducted.
p.000007: 1.60 Unexpected Adverse Drug Reaction
p.000007: An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g.,
p.000007: Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics
p.000007: for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for
p.000007: Expedited Reporting).
p.000007:
p.000007: 1.61 Vulnerable Subjects
p.000007: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether
p.000007: justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a
p.000007: hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure,
p.000007: such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees
p.000007: of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable
p.000007: subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons,
p.000007: patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and
p.000007: those incapable of giving consent.
p.000007: 1.62 Well-being (of the trial subjects)
p.000007: The physical and mental integrity of the subjects participating in a clinical trial.
p.000007: ADDENDUM
p.000007: 1.63 Certified Copy
p.000007: A copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated
p.000007: signature or by generation through a validated process) to have the same information, including data that describe the
p.000007: context, content, and structure, as the original.
p.000007: 1.64 Monitoring Plan
p.000007: A document that describes the strategy, methods, responsibilities, and requirements for monitoring
p.000007: the trial.
p.000007: 1.65 Validation of Computerized Systems
p.000007: A process of establishing and documenting that the specified requirements of a computerized system can be
p.000007: consistently fulfilled from design until decommissioning of the system or transition to a new system. The
p.000007: approach to validation should be based on a risk assessment that takes into consideration the intended use of the
p.000007: system and the potential of the system to affect human subject protection and reliability of trial results.
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000008: 8
p.000008:
...
Social / Fetus/Neonate
Searching for indicator fetus:
(return to top)
p.000016: subject’s participation in the trial and, if capable of doing so, has signed and personally dated the informed
p.000016: consent form, the witness should sign and personally date the consent form. By signing the consent form, the
p.000016: witness attests that the information in the consent form and any other written information was accurately
p.000016: explained to, and apparently understood by, the subject or the subject's legally acceptable representative, and that
p.000016: informed consent was freely given by the subject or the subject’s legally acceptable representative.
p.000016:
p.000016: 4.8.10 Both the informed consent discussion and the written informed consent form and any other written
p.000016: information to be provided to subjects should include explanations of the following:
p.000016: (a) That the trial involves research.
p.000016: (b) The purpose of the trial.
p.000016: (c) The trial treatment(s) and the probability for random assignment to each treatment.
p.000016: (d) The trial procedures to be followed, including all invasive procedures.
p.000016: (e) The subject's responsibilities.
p.000016: (f) Those aspects of the trial that are experimental.
p.000016: (g) The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo,
p.000016: fetus, or nursing infant.
p.000016: (h) The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be
p.000016: made aware of this.
p.000016: (i) The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their
p.000016: important potential benefits and risks.
p.000016: (j) The compensation and/or treatment available to the subject in the event of trial- related injury.
p.000016: (k) The anticipated prorated payment, if any, to the subject for participating in the trial.
p.000016: (l) The anticipated expenses, if any, to the subject for participating in the trial.
p.000016: (m) That the subject's participation in the trial is voluntary and that the subject may refuse to
p.000016: participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is
p.000016: otherwise entitled.
p.000016: (n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted
p.000016: direct access to the subject's original medical records for verification of clinical trial procedures and/or data,
p.000016: without violating the confidentiality of the subject, to the extent permitted by the applicable laws and
p.000016: regulations and that, by signing a written informed consent form, the subject or the subject's legally
p.000016: acceptable representative is authorizing such access.
p.000016: (o) That records identifying the subject will be kept confidential and, to the extent permitted by the
...
Social / Homeless Persons
Searching for indicator homeless:
(return to top)
p.000007: An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g.,
p.000007: Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics
p.000007: for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for
p.000007: Expedited Reporting).
p.000007:
p.000007: 1.61 Vulnerable Subjects
p.000007: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether
p.000007: justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a
p.000007: hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure,
p.000007: such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees
p.000007: of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable
p.000007: subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons,
p.000007: patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and
p.000007: those incapable of giving consent.
p.000007: 1.62 Well-being (of the trial subjects)
p.000007: The physical and mental integrity of the subjects participating in a clinical trial.
p.000007: ADDENDUM
p.000007: 1.63 Certified Copy
p.000007: A copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated
p.000007: signature or by generation through a validated process) to have the same information, including data that describe the
p.000007: context, content, and structure, as the original.
p.000007: 1.64 Monitoring Plan
p.000007: A document that describes the strategy, methods, responsibilities, and requirements for monitoring
p.000007: the trial.
p.000007: 1.65 Validation of Computerized Systems
p.000007: A process of establishing and documenting that the specified requirements of a computerized system can be
p.000007: consistently fulfilled from design until decommissioning of the system or transition to a new system. The
p.000007: approach to validation should be based on a risk assessment that takes into consideration the intended use of the
p.000007: system and the potential of the system to affect human subject protection and reliability of trial results.
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000008: 8
p.000008:
p.000008: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000008:
p.000008:
p.000008: 2. THE PRINCIPLES OF ICH GCP
p.000008:
...
Social / Infant
Searching for indicator infant:
(return to top)
p.000016: consent form, the witness should sign and personally date the consent form. By signing the consent form, the
p.000016: witness attests that the information in the consent form and any other written information was accurately
p.000016: explained to, and apparently understood by, the subject or the subject's legally acceptable representative, and that
p.000016: informed consent was freely given by the subject or the subject’s legally acceptable representative.
p.000016:
p.000016: 4.8.10 Both the informed consent discussion and the written informed consent form and any other written
p.000016: information to be provided to subjects should include explanations of the following:
p.000016: (a) That the trial involves research.
p.000016: (b) The purpose of the trial.
p.000016: (c) The trial treatment(s) and the probability for random assignment to each treatment.
p.000016: (d) The trial procedures to be followed, including all invasive procedures.
p.000016: (e) The subject's responsibilities.
p.000016: (f) Those aspects of the trial that are experimental.
p.000016: (g) The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo,
p.000016: fetus, or nursing infant.
p.000016: (h) The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be
p.000016: made aware of this.
p.000016: (i) The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their
p.000016: important potential benefits and risks.
p.000016: (j) The compensation and/or treatment available to the subject in the event of trial- related injury.
p.000016: (k) The anticipated prorated payment, if any, to the subject for participating in the trial.
p.000016: (l) The anticipated expenses, if any, to the subject for participating in the trial.
p.000016: (m) That the subject's participation in the trial is voluntary and that the subject may refuse to
p.000016: participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is
p.000016: otherwise entitled.
p.000016: (n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted
p.000016: direct access to the subject's original medical records for verification of clinical trial procedures and/or data,
p.000016: without violating the confidentiality of the subject, to the extent permitted by the applicable laws and
p.000016: regulations and that, by signing a written informed consent form, the subject or the subject's legally
p.000016: acceptable representative is authorizing such access.
p.000016: (o) That records identifying the subject will be kept confidential and, to the extent permitted by the
...
Social / Linguistic Proficiency
Searching for indicator language:
(return to top)
p.000015: approval/favourable opinion of the written informed consent form and any other written information to be provided to
p.000015: subjects.
p.000015:
p.000015: 4.8.2 The written informed consent form and any other written information to be provided to subjects should be
p.000015: revised whenever important new information becomes available that may be relevant to the subject’s consent. Any revised
p.000015: written informed consent form, and written information should receive the IRB/IEC's approval/favourable opinion in
p.000015: advance of use. The subject or the subject’s legally acceptable representative should be informed in a timely manner
p.000015: if new information becomes available that may be relevant to the subject’s willingness to continue
p.000015: participation in the trial. The communication of this information should be documented.
p.000015:
p.000015: 4.8.3 Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or
p.000015: to continue to participate in a trial.
p.000015:
p.000015: 4.8.4 None of the oral and written information concerning the trial, including the written informed
p.000015: consent form, should contain any language that causes the subject or the subject's legally acceptable
p.000015: representative to waive or to appear to waive any legal rights, or that releases or appears to release the
p.000015: investigator, the institution, the sponsor, or their agents from liability for negligence.
p.000015:
p.000015: 4.8.5 The investigator, or a person designated by the investigator, should fully inform the subject or,
p.000015: if the subject is unable to provide informed consent, the subject's legally acceptable representative, of
p.000015: all pertinent aspects of the trial including the written information and the approval/ favourable opinion by
p.000015: the IRB/IEC.
p.000015:
p.000015: 4.8.6 The language used in the oral and written information about the trial, including the written
p.000015: informed consent form, should be as non-technical as practical and should be understandable to the
p.000015: subject or the subject's legally acceptable representative and the impartial witness, where applicable.
p.000015:
p.000015: 4.8.7 Before informed consent may be obtained, the investigator, or a person designated by the investigator, should
p.000015: provide the subject or the subject's legally acceptable representative ample time and opportunity to inquire about
p.000015: details of the trial and to decide whether or not to participate in the trial. All questions about the trial
p.000015: should be answered to the satisfaction of the subject or the subject's legally acceptable representative.
p.000015:
p.000015: 4.8.8 Prior to a subject’s participation in the trial, the written informed consent form should be signed and
p.000015: personally dated by the subject or by the subject's legally acceptable representative, and by the person who
p.000015: conducted the informed consent discussion.
p.000015:
p.000015: 4.8.9 If a subject is unable to read or if a legally acceptable representative is unable to read, an impartial
p.000015: witness should be present during the entire informed consent discussion. After the written informed consent form and
p.000015: any other written information to be provided to subjects, is read and explained to the subject or the
p.000015: subject’s legally acceptable
p.000015:
p.000015:
...
Social / Marital Status
Searching for indicator single:
(return to top)
p.000001: 1.3 Amendment (to the protocol)
p.000001: See Protocol Amendment.
p.000001: 1.4 Applicable Regulatory Requirement(s)
p.000001: Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products.
p.000001: 1.5 Approval (in relation to Institutional Review Boards)
p.000001: The affirmative decision of the IRB that the clinical trial has been reviewed and may be conducted at
p.000001: the institution site within the constraints set forth by the IRB, the institution, Good Clinical Practice (GCP), and
p.000001: the applicable regulatory requirements.
p.000001: 1.6 Audit
p.000001: A systematic and independent examination of trial related activities and documents to determine whether the evaluated
p.000001: trial related activities were conducted, and the data were recorded, analyzed and accurately reported
p.000001: according to the protocol, sponsor's standard operating procedures (SOPs), Good Clinical Practice (GCP), and the
p.000001: applicable regulatory requirement(s).
p.000001: 1.7 Audit Certificate
p.000001: A declaration of confirmation by the auditor that an audit has taken place.
p.000001: 1.8 Audit Report
p.000001: A written evaluation by the sponsor's auditor of the results of the audit.
p.000001:
p.000001:
p.000001:
p.000001:
p.000001:
p.000001:
p.000001:
p.000002: 2
p.000002:
p.000002: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000002:
p.000002: 1.9 Audit Trail
p.000002: Documentation that allows reconstruction of the course of events.
p.000002: 1.10 Blinding/Masking
p.000002: A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s).
p.000002: Single-blinding usually refers to the subject(s) being unaware, and double- blinding usually refers to the
p.000002: subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment
p.000002: assignment(s).
p.000002: 1.11 Case Report Form (CRF)
p.000002: A printed, optical, or electronic document designed to record all of the protocol required information to
p.000002: be reported to the sponsor on each trial subject.
p.000002: 1.12 Clinical Trial/Study
p.000002: Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other
p.000002: pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an
p.000002: investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an
p.000002: investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial
p.000002: and clinical study are synonymous.
p.000002: 1.13 Clinical Trial/Study Report
p.000002: A written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent conducted in
p.000002: human subjects, in which the clinical and statistical description, presentations, and analyses are fully integrated
p.000002: into a single report (see the ICH Guideline for Structure and Content of Clinical Study Reports).
p.000002: 1.14 Comparator (Product)
p.000002: An investigational or marketed product (i.e., active control), or placebo, used as a reference in a clinical trial.
p.000002: 1.15 Compliance (in relation to trials)
p.000002: Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements, and the applicable
p.000002: regulatory requirements.
p.000002: 1.16 Confidentiality
p.000002: Prevention of disclosure, to other than authorized individuals, of a sponsor's proprietary information or of
p.000002: a subject's identity.
p.000002: 1.17 Contract
p.000002: A written, dated, and signed agreement between two or more involved parties that sets out any arrangements on
p.000002: delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol
p.000002: may serve as the basis of a contract.
p.000002: 1.18 Coordinating Committee
p.000002: A committee that a sponsor may organize to coordinate the conduct of a multicentre trial.
p.000002: 1.19 Coordinating Investigator
p.000002: An investigator assigned the responsibility for the coordination of investigators at different centres
p.000002: participating in a multicentre trial.
p.000002:
p.000002:
p.000002:
p.000002:
p.000003: 3
p.000003:
p.000003: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000003:
p.000003: 1.20 Contract Research Organization (CRO)
p.000003: A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or
p.000003: more of a sponsor's trial-related duties and functions.
p.000003: 1.21 Direct Access
...
p.000004: A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of
p.000004: individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal
p.000004: investigator. See also Subinvestigator.
p.000004: 1.35 Investigator/Institution
p.000004: An expression meaning "the investigator and/or institution, where required by the applicable regulatory
p.000004: requirements".
p.000004: 1.36 Investigator's Brochure
p.000004: A compilation of the clinical and nonclinical data on the investigational product(s) which is relevant to
p.000004: the study of the investigational product(s) in human subjects (see 7. Investigator’s Brochure).
p.000004: 1.37 Legally Acceptable Representative
p.000004: An individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective
p.000004: subject, to the subject's participation in the clinical trial.
p.000004:
p.000004:
p.000005: 5
p.000005:
p.000005: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000005:
p.000005: 1.38 Monitoring
p.000005: The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded,
p.000005: and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and
p.000005: the applicable regulatory requirement(s).
p.000005:
p.000005: 1.39 Monitoring Report
p.000005: A written report from the monitor to the sponsor after each site visit and/or other trial-related communication
p.000005: according to the sponsor’s SOPs.
p.000005:
p.000005: 1.40 Multicentre Trial
p.000005: A clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more
p.000005: than one investigator.
p.000005: 1.41 Nonclinical Study
p.000005: Biomedical studies not performed on human subjects.
p.000005: 1.42 Opinion (in relation to Independent Ethics Committee)
p.000005: The judgement and/or the advice provided by an Independent Ethics Committee (IEC).
p.000005: 1.43 Original Medical Record
p.000005: See Source Documents.
p.000005: 1.44 Protocol
p.000005: A document that describes the objective(s), design, methodology, statistical considerations, and organization of a
p.000005: trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other
p.000005: protocol referenced documents. Throughout the ICH GCP Guideline the term protocol refers to protocol and protocol
p.000005: amendments.
p.000005: 1.45 Protocol Amendment
p.000005: A written description of a change(s) to or formal clarification of a protocol.
p.000005: 1.46 Quality Assurance (QA)
p.000005: All those planned and systematic actions that are established to ensure that the trial is performed and the data are
p.000005: generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the
p.000005: applicable regulatory requirement(s).
p.000005: 1.47 Quality Control (QC)
p.000005: The operational techniques and activities undertaken within the quality assurance system to verify that the
p.000005: requirements for quality of the trial-related activities have been fulfilled.
p.000005: 1.48 Randomization
p.000005: The process of assigning trial subjects to treatment or control groups using an element of chance to determine the
...
p.000039: the effective and nontoxic dose findings in the same animal species should be compared (i.e., the therapeutic
p.000039: index should be discussed). The relevance of this information to the proposed human dosing should be addressed.
p.000039: Whenever possible, comparisons should be made in terms of blood/tissue levels rather than on a mg/kg basis.
p.000039:
p.000039: (a) Nonclinical Pharmacology
p.000039: A summary of the pharmacological aspects of the investigational product and, where appropriate, its
p.000039: significant metabolites studied in animals, should be included. Such a summary should incorporate studies
p.000039: that assess potential therapeutic activity (e.g., efficacy models, receptor binding, and specificity) as well as
p.000039: those that assess safety (e.g., special studies to assess pharmacological actions other than the intended
p.000039: therapeutic effect(s)).
p.000039: (b) Pharmacokinetics and Product Metabolism in Animals
p.000039: A summary of the pharmacokinetics and biological transformation and disposition of the investigational product in
p.000039: all species studied should be given. The discussion of the findings should address the absorption and the
p.000039: local and systemic bioavailability of the investigational product and its metabolites, and their relationship to the
p.000039: pharmacological and toxicological findings in animal species.
p.000039: (c) Toxicology
p.000039: A summary of the toxicological effects found in relevant studies conducted in different animal species should be
p.000039: described under the following headings where appropriate:
p.000039:
p.000039:
p.000040: 40
p.000040:
p.000040: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000040:
p.000040: - Single dose
p.000040: - Repeated dose
p.000040: - Carcinogenicity
p.000040: - Special studies (e.g., irritancy and sensitisation)
p.000040: - Reproductive toxicity
p.000040: - Genotoxicity (mutagenicity)
p.000040: 7.3.6 Effects in Humans Introduction:
p.000040: A thorough discussion of the known effects of the investigational product(s) in humans should be provided,
p.000040: including information on pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy,
p.000040: and other pharmacological activities. Where possible, a summary of each completed clinical trial should be
p.000040: provided. Information should also be provided regarding results of any use of the investigational product(s) other
p.000040: than from in clinical trials, such as from experience during marketing.
p.000040: (a) Pharmacokinetics and Product Metabolism in Humans
p.000040: - A summary of information on the pharmacokinetics of the investigational product(s) should be
p.000040: presented, including the following, if available:
p.000040: - Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, distribution, and
p.000040: elimination).
p.000040: - Bioavailability of the investigational product (absolute, where possible, and/or relative) using a
p.000040: reference dosage form.
p.000040: - Population subgroups (e.g., gender, age, and impaired organ function).
p.000040: - Interactions (e.g., product-product interactions and effects of food).
p.000040: - Other pharmacokinetic data (e.g., results of population studies performed within clinical trial(s).
p.000040: (b) Safety and Efficacy
...
Social / Presence of Coercion
Searching for indicator coerce:
(return to top)
p.000015:
p.000015: 4.8 Informed Consent of Trial Subjects
p.000015:
p.000015: 4.8.1 In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory
p.000015: requirement(s), and should adhere to GCP and to the ethical principles that have their origin in the
p.000015: Declaration of Helsinki. Prior to the beginning of the trial, the investigator should have the IRB/IEC's written
p.000015: approval/favourable opinion of the written informed consent form and any other written information to be provided to
p.000015: subjects.
p.000015:
p.000015: 4.8.2 The written informed consent form and any other written information to be provided to subjects should be
p.000015: revised whenever important new information becomes available that may be relevant to the subject’s consent. Any revised
p.000015: written informed consent form, and written information should receive the IRB/IEC's approval/favourable opinion in
p.000015: advance of use. The subject or the subject’s legally acceptable representative should be informed in a timely manner
p.000015: if new information becomes available that may be relevant to the subject’s willingness to continue
p.000015: participation in the trial. The communication of this information should be documented.
p.000015:
p.000015: 4.8.3 Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or
p.000015: to continue to participate in a trial.
p.000015:
p.000015: 4.8.4 None of the oral and written information concerning the trial, including the written informed
p.000015: consent form, should contain any language that causes the subject or the subject's legally acceptable
p.000015: representative to waive or to appear to waive any legal rights, or that releases or appears to release the
p.000015: investigator, the institution, the sponsor, or their agents from liability for negligence.
p.000015:
p.000015: 4.8.5 The investigator, or a person designated by the investigator, should fully inform the subject or,
p.000015: if the subject is unable to provide informed consent, the subject's legally acceptable representative, of
p.000015: all pertinent aspects of the trial including the written information and the approval/ favourable opinion by
p.000015: the IRB/IEC.
p.000015:
p.000015: 4.8.6 The language used in the oral and written information about the trial, including the written
p.000015: informed consent form, should be as non-technical as practical and should be understandable to the
p.000015: subject or the subject's legally acceptable representative and the impartial witness, where applicable.
p.000015:
...
Social / Racial Minority
Searching for indicator minority:
(return to top)
p.000007: 1.60 Unexpected Adverse Drug Reaction
p.000007: An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g.,
p.000007: Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics
p.000007: for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for
p.000007: Expedited Reporting).
p.000007:
p.000007: 1.61 Vulnerable Subjects
p.000007: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether
p.000007: justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a
p.000007: hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure,
p.000007: such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees
p.000007: of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable
p.000007: subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons,
p.000007: patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and
p.000007: those incapable of giving consent.
p.000007: 1.62 Well-being (of the trial subjects)
p.000007: The physical and mental integrity of the subjects participating in a clinical trial.
p.000007: ADDENDUM
p.000007: 1.63 Certified Copy
p.000007: A copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated
p.000007: signature or by generation through a validated process) to have the same information, including data that describe the
p.000007: context, content, and structure, as the original.
p.000007: 1.64 Monitoring Plan
p.000007: A document that describes the strategy, methods, responsibilities, and requirements for monitoring
p.000007: the trial.
p.000007: 1.65 Validation of Computerized Systems
p.000007: A process of establishing and documenting that the specified requirements of a computerized system can be
p.000007: consistently fulfilled from design until decommissioning of the system or transition to a new system. The
p.000007: approach to validation should be based on a risk assessment that takes into consideration the intended use of the
p.000007: system and the potential of the system to affect human subject protection and reliability of trial results.
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000008: 8
p.000008:
p.000008: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000008:
p.000008:
...
Social / Soldier
Searching for indicator armed forces:
(return to top)
p.000007:
p.000007: 1.58 Subject Identification Code
p.000007: A unique identifier assigned by the investigator to each trial subject to protect the subject's identity
p.000007: and used in lieu of the subject's name when the investigator reports adverse events and/or other trial
p.000007: related data.
p.000007: 1.59 Trial Site
p.000007: The location(s) where trial-related activities are actually conducted.
p.000007: 1.60 Unexpected Adverse Drug Reaction
p.000007: An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g.,
p.000007: Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics
p.000007: for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for
p.000007: Expedited Reporting).
p.000007:
p.000007: 1.61 Vulnerable Subjects
p.000007: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether
p.000007: justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a
p.000007: hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure,
p.000007: such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees
p.000007: of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable
p.000007: subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons,
p.000007: patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and
p.000007: those incapable of giving consent.
p.000007: 1.62 Well-being (of the trial subjects)
p.000007: The physical and mental integrity of the subjects participating in a clinical trial.
p.000007: ADDENDUM
p.000007: 1.63 Certified Copy
p.000007: A copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated
p.000007: signature or by generation through a validated process) to have the same information, including data that describe the
p.000007: context, content, and structure, as the original.
p.000007: 1.64 Monitoring Plan
p.000007: A document that describes the strategy, methods, responsibilities, and requirements for monitoring
p.000007: the trial.
p.000007: 1.65 Validation of Computerized Systems
p.000007: A process of establishing and documenting that the specified requirements of a computerized system can be
p.000007: consistently fulfilled from design until decommissioning of the system or transition to a new system. The
...
Social / Trade Union Membership
Searching for indicator union:
(return to top)
p.000039: 39
p.000039: 7.3.2 Summary
p.000039: 39
p.000039: 7.3.3 Introduction
p.000039: 39
p.000039: 7.3.4 Physical, Chemical, and Pharmaceutical Properties and Formulation 39
p.000039: 7.3.5 Nonclinical Studies
p.000039: 39
p.000039: 7.3.6 Effects in Humans
p.000041: 41
p.000041: 7.3.7 Summary of Data and Guidance for the Investigator 42
p.000041: 7.4 APPENDIX 1:
p.000043: 43
p.000043: 7.5 APPENDIX 2:
p.000044: 44
p.000044: 8. ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL 45
p.000044: 8.1 Introduction
p.000045: 45
p.000045: 8.2 Before the Clinical Phase of the Trial Commences
p.000046: 46
p.000046: 8.3 During the Clinical Conduct of the Trial
p.000053: 53
p.000053: 8.4 After Completion or Termination of the Trial
p.000059: 59
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059: iii
p.000059:
p.000059:
p.000059:
p.000059: INTEGRATED ADDENDUM TO ICH E6(R1): GUIDELINE FOR GOOD CLINICAL PRACTICE ICH
p.000059: E6(R2)
p.000059:
p.000059: INTRODUCTION
p.000059: Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing,
p.000059: conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this
p.000059: standard provides public assurance that the rights, safety and well-being of trial subjects are protected, consistent
p.000059: with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are
p.000059: credible.
p.000059: The objective of this ICH GCP Guideline is to provide a unified standard for the European Union (EU), Japan and the
p.000059: United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these
p.000059: jurisdictions.
p.000059: The guideline was developed with consideration of the current good clinical practices of the European Union, Japan,
p.000059: and the United States, as well as those of Australia, Canada, the Nordic countries and the World Health
p.000059: Organization (WHO).
p.000059: This guideline should be followed when generating clinical trial data that are intended to be submitted to regulatory
p.000059: authorities.
p.000059: The principles established in this guideline may also be applied to other clinical
p.000059: investigations that may have an impact on the safety and well-being of human subjects.
p.000059: ADDENDUM
p.000059: Since the development of the ICH GCP Guideline, the scale, complexity, and cost of clinical trials have increased.
p.000059: Evolutions in technology and risk management processes offer new opportunities to increase efficiency and focus
p.000059: on relevant activities. When the original ICH E6(R1) text was prepared, clinical trials were performed in a
p.000059: largely paper-based process. Advances in use of electronic data recording and reporting facilitate implementation of
p.000059: other approaches. For example, centralized monitoring can now offer a greater advantage, to a broader
p.000059: range of trials than is suggested in the original text. Therefore, this guideline has been amended to
p.000059: encourage implementation of improved and more efficient approaches to clinical trial design, conduct,
p.000059: oversight, recording and reporting while continuing to ensure human subject protection and reliability of trial
p.000059: results. Standards regarding electronic records and essential documents intended to increase clinical trial quality
p.000059: and efficiency have also been updated.
p.000059: This guideline should be read in conjunction with other ICH guidelines relevant to the conduct of
p.000059: clinical trials (e.g., E2A (clinical safety data management), E3 (clinical study reporting), E7 (geriatric
p.000059: populations), E8 (general considerations for clinical trials), E9 (statistical principles), and E11 (pediatric
p.000059: populations)).
p.000059: This ICH GCP Guideline Integrated Addendum provides a unified standard for the European Union, Japan, the United
p.000059: States, Canada, and Switzerland to facilitate the mutual acceptance of data from clinical trials by the regulatory
p.000059: authorities in these jurisdictions. In the event of any conflict between the E6(R1) text and the E6(R2) addendum text,
p.000059: the E6(R2) addendum text should take priority.
p.000059:
p.000059:
p.000059:
p.000059:
p.000001: 1
p.000001:
p.000001: 1. GLOSSARY
p.000001:
p.000001: 1.1 Adverse Drug Reaction (ADR)
p.000001: In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as
p.000001: the therapeutic dose(s) may not be established: all noxious and unintended responses to a medicinal
p.000001: product related to any dose should be considered adverse drug reactions. The phrase responses to a medicinal
p.000001: product means that a causal relationship between a medicinal product and an adverse event is at least a reasonable
p.000001: possibility, i.e., the relationship cannot be ruled out.
p.000001: Regarding marketed medicinal products: a response to a drug which is noxious and unintended and which occurs at
p.000001: doses normally used in man for prophylaxis, diagnosis, or therapy of diseases or for modification of
p.000001: physiological function (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for
p.000001: Expedited Reporting).
p.000001: 1.2 Adverse Event (AE)
p.000001: Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical
p.000001: product and which does not necessarily have a causal relationship with this treatment. An adverse event
...
Social / Unemployment
Searching for indicator unemployed:
(return to top)
p.000007: and used in lieu of the subject's name when the investigator reports adverse events and/or other trial
p.000007: related data.
p.000007: 1.59 Trial Site
p.000007: The location(s) where trial-related activities are actually conducted.
p.000007: 1.60 Unexpected Adverse Drug Reaction
p.000007: An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g.,
p.000007: Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics
p.000007: for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for
p.000007: Expedited Reporting).
p.000007:
p.000007: 1.61 Vulnerable Subjects
p.000007: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether
p.000007: justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a
p.000007: hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure,
p.000007: such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees
p.000007: of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable
p.000007: subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons,
p.000007: patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and
p.000007: those incapable of giving consent.
p.000007: 1.62 Well-being (of the trial subjects)
p.000007: The physical and mental integrity of the subjects participating in a clinical trial.
p.000007: ADDENDUM
p.000007: 1.63 Certified Copy
p.000007: A copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated
p.000007: signature or by generation through a validated process) to have the same information, including data that describe the
p.000007: context, content, and structure, as the original.
p.000007: 1.64 Monitoring Plan
p.000007: A document that describes the strategy, methods, responsibilities, and requirements for monitoring
p.000007: the trial.
p.000007: 1.65 Validation of Computerized Systems
p.000007: A process of establishing and documenting that the specified requirements of a computerized system can be
p.000007: consistently fulfilled from design until decommissioning of the system or transition to a new system. The
p.000007: approach to validation should be based on a risk assessment that takes into consideration the intended use of the
...
Social / Youth/Minors
Searching for indicator minor:
(return to top)
p.000010: regulatory requirement(s).
p.000010:
p.000010: 3.2.3 An IRB/IEC should make its decisions at announced meetings at which at least a quorum, as
p.000010: stipulated in its written operating procedures, is present.
p.000010:
p.000010: 3.2.4 Only members who participate in the IRB/IEC review and discussion should vote/provide
p.000010: their opinion and/or advise.
p.000010:
p.000010: 3.2.5 The investigator may provide information on any aspect of the trial, but should not participate
p.000010: in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC.
p.000010:
p.000010: 3.2.6 An IRB/IEC may invite nonmembers with expertise in special areas for assistance.
p.000010:
p.000010: 3.3 Procedures
p.000010: The IRB/IEC should establish, document in writing, and follow its procedures, which should include:
p.000010:
p.000010:
p.000011: 11
p.000011:
p.000011: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000011:
p.000011: 3.3.1 Determining its composition (names and qualifications of the members) and the authority under which it is
p.000011: established.
p.000011:
p.000011: 3.3.2 Scheduling, notifying its members of, and conducting its meetings.
p.000011:
p.000011: 3.3.3 Conducting initial and continuing review of trials.
p.000011:
p.000011: 3.3.4 Determining the frequency of continuing review, as appropriate.
p.000011:
p.000011: 3.3.5 Providing, according to the applicable regulatory requirements, expedited review and
p.000011: approval/favourable opinion of minor change(s) in ongoing trials that have the approval/favourable
p.000011: opinion of the IRB/IEC.
p.000011:
p.000011: 3.3.6 Specifying that no subject should be admitted to a trial before the IRB/IEC issues its written
p.000011: approval/favourable opinion of the trial.
p.000011:
p.000011: 3.3.7 Specifying that no deviations from, or changes of, the protocol should be initiated without
p.000011: prior written IRB/IEC approval/favourable opinion of an appropriate amendment, except when
p.000011: necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or
p.000011: administrative aspects of the trial (e.g., change of monitor(s), telephone number(s)) (see 4.5.2).
p.000011:
p.000011: 3.3.8 Specifying that the investigator should promptly report to the IRB/IEC:
p.000011: (a) Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial subjects (see 3.3.7,
p.000011: 4.5.2, 4.5.4).
p.000011: (b) Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial (see 4.10.2).
p.000011: (c) All adverse drug reactions (ADRs) that are both serious and unexpected.
p.000011: (d) New information that may affect adversely the safety of the subjects or the conduct of the trial.
p.000011:
p.000011: 3.3.9 Ensuring that the IRB/IEC promptly notify in writing the investigator/institution
p.000011: concerning:
p.000011: (a) Its trial-related decisions/opinions.
p.000011: (b) The reasons for its decisions/opinions.
...
Social / education
Searching for indicator education:
(return to top)
p.000008:
p.000008: 2.1 Clinical trials should be conducted in accordance with the ethical principles that have their
p.000008: origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory
p.000008: requirement(s).
p.000008:
p.000008: 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated
p.000008: benefit for the individual trial subject and society. A trial should be initiated and continued only if the
p.000008: anticipated benefits justify the risks.
p.000008:
p.000008: 2.3 The rights, safety, and well-being of the trial subjects are the most important
p.000008: considerations and should prevail over interests of science and society.
p.000008:
p.000008: 2.4 The available nonclinical and clinical information on an investigational product should be adequate to
p.000008: support the proposed clinical trial.
p.000008:
p.000008: 2.5 Clinical trials should be scientifically sound, and described in a clear, detailed protocol.
p.000008:
p.000008: 2.6 A trial should be conducted in compliance with the protocol that has received prior
p.000008: institutional review board (IRB)/independent ethics committee (IEC)
p.000008: approval/favourable opinion.
p.000008:
p.000008: 2.7 The medical care given to, and medical decisions made on behalf of, subjects should always be
p.000008: the responsibility of a qualified physician or, when appropriate, of a qualified dentist.
p.000008:
p.000008: 2.8 Each individual involved in conducting a trial should be qualified by education, training, and experience to
p.000008: perform his or her respective task(s).
p.000008:
p.000008: 2.9 Freely given informed consent should be obtained from every subject prior to clinical trial
p.000008: participation.
p.000008:
p.000008: 2.10 All clinical trial information should be recorded, handled, and stored in a way that allows its accurate
p.000008: reporting, interpretation and verification.
p.000008: ADDENDUM
p.000008: This principle applies to all records referenced in this guideline, irrespective of the type of media used.
p.000008: 2.11 The confidentiality of records that could identify subjects should be protected, respecting the privacy and
p.000008: confidentiality rules in accordance with the applicable regulatory requirement(s).
p.000008:
p.000008: 2.12 Investigational products should be manufactured, handled, and stored in accordance with applicable good
p.000008: manufacturing practice (GMP). They should be used in accordance with the approved protocol.
p.000008:
p.000008:
p.000008:
p.000008:
p.000008:
p.000009: 9
p.000009:
p.000009: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000009:
p.000009: 2.13 Systems with procedures that assure the quality of every aspect of the trial should be
p.000009: implemented.
p.000009: ADDENDUM
p.000009: Aspects of the trial that are essential to ensure human subject protection and reliability of trial results should be
p.000009: the focus of such systems.
p.000009:
p.000009: 3. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)
p.000009:
p.000009: 3.1 Responsibilities
p.000009:
...
p.000011: 4.5.2, 4.5.4).
p.000011: (b) Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial (see 4.10.2).
p.000011: (c) All adverse drug reactions (ADRs) that are both serious and unexpected.
p.000011: (d) New information that may affect adversely the safety of the subjects or the conduct of the trial.
p.000011:
p.000011: 3.3.9 Ensuring that the IRB/IEC promptly notify in writing the investigator/institution
p.000011: concerning:
p.000011: (a) Its trial-related decisions/opinions.
p.000011: (b) The reasons for its decisions/opinions.
p.000011: (c) Procedures for appeal of its decisions/opinions.
p.000011:
p.000011: 3.4 Records
p.000011: The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists, lists of
p.000011: occupations/affiliations of members, submitted documents, minutes of meetings, and correspondence) for
p.000011: a period of at least 3-years after completion of the trial and make them available upon request from the
p.000011: regulatory authority(ies).
p.000011: The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its written
p.000011: procedures and membership lists.
p.000011:
p.000011:
p.000011:
p.000011:
p.000011:
p.000011:
p.000012: 12
p.000012:
p.000012: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000012:
p.000012: 4. INVESTIGATOR
p.000012:
p.000012: 4.1 Investigator's Qualifications and Agreements
p.000012:
p.000012: 4.1.1 The investigator(s) should be qualified by education, training, and experience to assume responsibility for
p.000012: the proper conduct of the trial, should meet all the qualifications specified by the applicable
p.000012: regulatory requirement(s), and should provide evidence of such qualifications through up-to-date
p.000012: curriculum vitae and/or other relevant documentation requested by the sponsor, the IRB/IEC,
p.000012: and/or the regulatory authority(ies).
p.000012:
p.000012: 4.1.2 The investigator should be thoroughly familiar with the appropriate use of the
p.000012: investigational product(s), as described in the protocol, in the current Investigator's Brochure, in the
p.000012: product information and in other information sources provided by the sponsor.
p.000012:
p.000012: 4.1.3 The investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements.
p.000012:
p.000012: 4.1.4 The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by
p.000012: the appropriate regulatory authority(ies).
p.000012:
p.000012: 4.1.5 The investigator should maintain a list of appropriately qualified persons to whom the investigator
p.000012: has delegated significant trial-related duties.
p.000012:
p.000012: 4.2 Adequate Resources
p.000012:
p.000012: 4.2.1 The investigator should be able to demonstrate (e.g., based on retrospective data) a potential
p.000012: for recruiting the required number of suitable subjects within the agreed recruitment period.
p.000012:
p.000012: 4.2.2 The investigator should have sufficient time to properly conduct and complete the trial within the agreed
p.000012: trial period.
p.000012:
...
Social / embryo
Searching for indicator embryo:
(return to top)
p.000016:
p.000016: representative, and after the subject or the subject’s legally acceptable representative has orally consented to the
p.000016: subject’s participation in the trial and, if capable of doing so, has signed and personally dated the informed
p.000016: consent form, the witness should sign and personally date the consent form. By signing the consent form, the
p.000016: witness attests that the information in the consent form and any other written information was accurately
p.000016: explained to, and apparently understood by, the subject or the subject's legally acceptable representative, and that
p.000016: informed consent was freely given by the subject or the subject’s legally acceptable representative.
p.000016:
p.000016: 4.8.10 Both the informed consent discussion and the written informed consent form and any other written
p.000016: information to be provided to subjects should include explanations of the following:
p.000016: (a) That the trial involves research.
p.000016: (b) The purpose of the trial.
p.000016: (c) The trial treatment(s) and the probability for random assignment to each treatment.
p.000016: (d) The trial procedures to be followed, including all invasive procedures.
p.000016: (e) The subject's responsibilities.
p.000016: (f) Those aspects of the trial that are experimental.
p.000016: (g) The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo,
p.000016: fetus, or nursing infant.
p.000016: (h) The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be
p.000016: made aware of this.
p.000016: (i) The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their
p.000016: important potential benefits and risks.
p.000016: (j) The compensation and/or treatment available to the subject in the event of trial- related injury.
p.000016: (k) The anticipated prorated payment, if any, to the subject for participating in the trial.
p.000016: (l) The anticipated expenses, if any, to the subject for participating in the trial.
p.000016: (m) That the subject's participation in the trial is voluntary and that the subject may refuse to
p.000016: participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is
p.000016: otherwise entitled.
p.000016: (n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted
p.000016: direct access to the subject's original medical records for verification of clinical trial procedures and/or data,
p.000016: without violating the confidentiality of the subject, to the extent permitted by the applicable laws and
p.000016: regulations and that, by signing a written informed consent form, the subject or the subject's legally
p.000016: acceptable representative is authorizing such access.
...
Social / employees
Searching for indicator employees:
(return to top)
p.000006: product(s) or as a control.
p.000006:
p.000006:
p.000006:
p.000006:
p.000007: 7
p.000007:
p.000007: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000007:
p.000007: 1.58 Subject Identification Code
p.000007: A unique identifier assigned by the investigator to each trial subject to protect the subject's identity
p.000007: and used in lieu of the subject's name when the investigator reports adverse events and/or other trial
p.000007: related data.
p.000007: 1.59 Trial Site
p.000007: The location(s) where trial-related activities are actually conducted.
p.000007: 1.60 Unexpected Adverse Drug Reaction
p.000007: An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g.,
p.000007: Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics
p.000007: for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for
p.000007: Expedited Reporting).
p.000007:
p.000007: 1.61 Vulnerable Subjects
p.000007: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether
p.000007: justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a
p.000007: hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure,
p.000007: such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees
p.000007: of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable
p.000007: subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons,
p.000007: patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and
p.000007: those incapable of giving consent.
p.000007: 1.62 Well-being (of the trial subjects)
p.000007: The physical and mental integrity of the subjects participating in a clinical trial.
p.000007: ADDENDUM
p.000007: 1.63 Certified Copy
p.000007: A copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated
p.000007: signature or by generation through a validated process) to have the same information, including data that describe the
p.000007: context, content, and structure, as the original.
p.000007: 1.64 Monitoring Plan
p.000007: A document that describes the strategy, methods, responsibilities, and requirements for monitoring
p.000007: the trial.
p.000007: 1.65 Validation of Computerized Systems
p.000007: A process of establishing and documenting that the specified requirements of a computerized system can be
...
Social / gender
Searching for indicator gender:
(return to top)
p.000039: (c) Toxicology
p.000039: A summary of the toxicological effects found in relevant studies conducted in different animal species should be
p.000039: described under the following headings where appropriate:
p.000039:
p.000039:
p.000040: 40
p.000040:
p.000040: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000040:
p.000040: - Single dose
p.000040: - Repeated dose
p.000040: - Carcinogenicity
p.000040: - Special studies (e.g., irritancy and sensitisation)
p.000040: - Reproductive toxicity
p.000040: - Genotoxicity (mutagenicity)
p.000040: 7.3.6 Effects in Humans Introduction:
p.000040: A thorough discussion of the known effects of the investigational product(s) in humans should be provided,
p.000040: including information on pharmacokinetics, metabolism, pharmacodynamics, dose response, safety, efficacy,
p.000040: and other pharmacological activities. Where possible, a summary of each completed clinical trial should be
p.000040: provided. Information should also be provided regarding results of any use of the investigational product(s) other
p.000040: than from in clinical trials, such as from experience during marketing.
p.000040: (a) Pharmacokinetics and Product Metabolism in Humans
p.000040: - A summary of information on the pharmacokinetics of the investigational product(s) should be
p.000040: presented, including the following, if available:
p.000040: - Pharmacokinetics (including metabolism, as appropriate, and absorption, plasma protein binding, distribution, and
p.000040: elimination).
p.000040: - Bioavailability of the investigational product (absolute, where possible, and/or relative) using a
p.000040: reference dosage form.
p.000040: - Population subgroups (e.g., gender, age, and impaired organ function).
p.000040: - Interactions (e.g., product-product interactions and effects of food).
p.000040: - Other pharmacokinetic data (e.g., results of population studies performed within clinical trial(s).
p.000040: (b) Safety and Efficacy
p.000040: A summary of information should be provided about the investigational product's/products'
p.000040: (including metabolites, where appropriate) safety, pharmacodynamics, efficacy, and dose response that were obtained
p.000040: from preceding trials in humans (healthy volunteers and/or patients). The implications of this information should be
p.000040: discussed. In cases where a number of clinical trials have been completed, the use of summaries of safety
p.000040: and efficacy across multiple trials by indications in subgroups may provide a clear presentation of the data. Tabular
p.000040: summaries of adverse drug reactions for all the clinical trials (including those for all the studied
p.000040: indications) would be useful. Important differences in adverse drug reaction patterns/incidences across indications
p.000040: or subgroups should be discussed.
p.000040: The IB should provide a description of the possible risks and adverse drug reactions to be anticipated on the basis
p.000040: of prior experiences with the product under investigation and with related products. A description should also
p.000040: be provided of the precautions or special monitoring to be done as part of the investigational use of the product(s).
...
Social / philosophical differences/differences of opinion
Searching for indicator opinion:
(return to top)
p.000003: trials that provides assurance that the data and reported results are credible and accurate, and that the rights,
p.000003: integrity, and confidentiality of trial subjects are protected.
p.000003: 1.25 Independent Data-Monitoring Committee (IDMC) (Data and Safety Monitoring Board, Monitoring Committee,
p.000003: Data Monitoring Committee)
p.000003: An independent data-monitoring committee that may be established by the sponsor to assess at intervals the progress of
p.000003: a clinical trial, the safety data, and the critical efficacy endpoints, and to recommend to the sponsor whether to
p.000003: continue, modify, or stop a trial.
p.000003: 1.26 Impartial Witness
p.000003: A person, who is independent of the trial, who cannot be unfairly influenced by people involved with the trial, who
p.000003: attends the informed consent process if the subject or the subject’s legally acceptable representative cannot read,
p.000003: and who reads the informed consent form and any other written information supplied to the subject.
p.000003: 1.27 Independent Ethics Committee (IEC)
p.000003: An independent body (a review board or a committee, institutional, regional, national, or supranational),
p.000003: constituted of medical professionals and non-medical members, whose responsibility it is to ensure the
p.000003: protection of the rights, safety and well-being of human subjects involved in a trial and to provide public assurance
p.000003: of that protection, by, among other things, reviewing and approving/providing favourable opinion on, the trial
p.000003: protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and
p.000003: documenting informed consent of the trial subjects.
p.000003: The legal status, composition, function, operations and regulatory requirements pertaining to Independent
p.000003: Ethics Committees may differ among countries, but should allow the Independent Ethics Committee to act in agreement
p.000003: with GCP as described in this guideline.
p.000003:
p.000003:
p.000003:
p.000003:
p.000003:
p.000004: 4
p.000004:
p.000004: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000004:
p.000004: 1.28 Informed Consent
p.000004: A process by which a subject voluntarily confirms his or her willingness to participate in a particular
p.000004: trial, after having been informed of all aspects of the trial that are relevant to the subject's
p.000004: decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form.
p.000004: 1.29 Inspection
p.000004: The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any
p.000004: other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located
...
p.000004: 1.35 Investigator/Institution
p.000004: An expression meaning "the investigator and/or institution, where required by the applicable regulatory
p.000004: requirements".
p.000004: 1.36 Investigator's Brochure
p.000004: A compilation of the clinical and nonclinical data on the investigational product(s) which is relevant to
p.000004: the study of the investigational product(s) in human subjects (see 7. Investigator’s Brochure).
p.000004: 1.37 Legally Acceptable Representative
p.000004: An individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective
p.000004: subject, to the subject's participation in the clinical trial.
p.000004:
p.000004:
p.000005: 5
p.000005:
p.000005: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000005:
p.000005: 1.38 Monitoring
p.000005: The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded,
p.000005: and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and
p.000005: the applicable regulatory requirement(s).
p.000005:
p.000005: 1.39 Monitoring Report
p.000005: A written report from the monitor to the sponsor after each site visit and/or other trial-related communication
p.000005: according to the sponsor’s SOPs.
p.000005:
p.000005: 1.40 Multicentre Trial
p.000005: A clinical trial conducted according to a single protocol but at more than one site, and therefore, carried out by more
p.000005: than one investigator.
p.000005: 1.41 Nonclinical Study
p.000005: Biomedical studies not performed on human subjects.
p.000005: 1.42 Opinion (in relation to Independent Ethics Committee)
p.000005: The judgement and/or the advice provided by an Independent Ethics Committee (IEC).
p.000005: 1.43 Original Medical Record
p.000005: See Source Documents.
p.000005: 1.44 Protocol
p.000005: A document that describes the objective(s), design, methodology, statistical considerations, and organization of a
p.000005: trial. The protocol usually also gives the background and rationale for the trial, but these could be provided in other
p.000005: protocol referenced documents. Throughout the ICH GCP Guideline the term protocol refers to protocol and protocol
p.000005: amendments.
p.000005: 1.45 Protocol Amendment
p.000005: A written description of a change(s) to or formal clarification of a protocol.
p.000005: 1.46 Quality Assurance (QA)
p.000005: All those planned and systematic actions that are established to ensure that the trial is performed and the data are
p.000005: generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the
p.000005: applicable regulatory requirement(s).
p.000005: 1.47 Quality Control (QC)
p.000005: The operational techniques and activities undertaken within the quality assurance system to verify that the
p.000005: requirements for quality of the trial-related activities have been fulfilled.
p.000005: 1.48 Randomization
p.000005: The process of assigning trial subjects to treatment or control groups using an element of chance to determine the
p.000005: assignments in order to reduce bias.
p.000005: 1.49 Regulatory Authorities
p.000005: Bodies having the power to regulate. In the ICH GCP Guideline the expression Regulatory Authorities
...
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000008: 8
p.000008:
p.000008: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000008:
p.000008:
p.000008: 2. THE PRINCIPLES OF ICH GCP
p.000008:
p.000008: 2.1 Clinical trials should be conducted in accordance with the ethical principles that have their
p.000008: origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory
p.000008: requirement(s).
p.000008:
p.000008: 2.2 Before a trial is initiated, foreseeable risks and inconveniences should be weighed against the anticipated
p.000008: benefit for the individual trial subject and society. A trial should be initiated and continued only if the
p.000008: anticipated benefits justify the risks.
p.000008:
p.000008: 2.3 The rights, safety, and well-being of the trial subjects are the most important
p.000008: considerations and should prevail over interests of science and society.
p.000008:
p.000008: 2.4 The available nonclinical and clinical information on an investigational product should be adequate to
p.000008: support the proposed clinical trial.
p.000008:
p.000008: 2.5 Clinical trials should be scientifically sound, and described in a clear, detailed protocol.
p.000008:
p.000008: 2.6 A trial should be conducted in compliance with the protocol that has received prior
p.000008: institutional review board (IRB)/independent ethics committee (IEC)
p.000008: approval/favourable opinion.
p.000008:
p.000008: 2.7 The medical care given to, and medical decisions made on behalf of, subjects should always be
p.000008: the responsibility of a qualified physician or, when appropriate, of a qualified dentist.
p.000008:
p.000008: 2.8 Each individual involved in conducting a trial should be qualified by education, training, and experience to
p.000008: perform his or her respective task(s).
p.000008:
p.000008: 2.9 Freely given informed consent should be obtained from every subject prior to clinical trial
p.000008: participation.
p.000008:
p.000008: 2.10 All clinical trial information should be recorded, handled, and stored in a way that allows its accurate
p.000008: reporting, interpretation and verification.
p.000008: ADDENDUM
p.000008: This principle applies to all records referenced in this guideline, irrespective of the type of media used.
p.000008: 2.11 The confidentiality of records that could identify subjects should be protected, respecting the privacy and
p.000008: confidentiality rules in accordance with the applicable regulatory requirement(s).
p.000008:
p.000008: 2.12 Investigational products should be manufactured, handled, and stored in accordance with applicable good
p.000008: manufacturing practice (GMP). They should be used in accordance with the approved protocol.
p.000008:
p.000008:
p.000008:
p.000008:
p.000008:
p.000009: 9
p.000009:
p.000009: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000009:
p.000009: 2.13 Systems with procedures that assure the quality of every aspect of the trial should be
p.000009: implemented.
p.000009: ADDENDUM
p.000009: Aspects of the trial that are essential to ensure human subject protection and reliability of trial results should be
p.000009: the focus of such systems.
p.000009:
p.000009: 3. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC)
p.000009:
p.000009: 3.1 Responsibilities
p.000009:
p.000009: 3.1.1 An IRB/IEC should safeguard the rights, safety, and well-being of all trial subjects. Special
p.000009: attention should be paid to trials that may include vulnerable subjects.
p.000009:
p.000009: 3.1.2 The IRB/IEC should obtain the following documents:
p.000009: trial protocol(s)/amendment(s), written informed consent form(s) and consent form updates that the investigator
p.000009: proposes for use in the trial, subject recruitment procedures (e.g., advertisements), written information to be
p.000009: provided to subjects, Investigator's Brochure (IB), available safety information, information about
p.000009: payments and compensation available to subjects, the investigator’s current curriculum vitae and/or
p.000009: other documentation evidencing qualifications, and any other documents that the IRB/IEC may need to
p.000009: fulfil its responsibilities.
p.000009: The IRB/IEC should review a proposed clinical trial within a reasonable time and document its views in
p.000009: writing, clearly identifying the trial, the documents reviewed and the dates for the following:
p.000009: - approval/favourable opinion;
p.000009: - modifications required prior to its approval/favourable opinion;
p.000009: - disapproval / negative opinion; and
p.000009: - termination/suspension of any prior approval/favourable opinion.
p.000009:
p.000009: 3.1.3 The IRB/IEC should consider the qualifications of the investigator for the proposed trial, as documented by a
p.000009: current curriculum vitae and/or by any other relevant documentation the IRB/IEC requests.
p.000009:
p.000009: 3.1.4 The IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the
p.000009: degree of risk to human subjects, but at least once per year.
p.000009:
p.000009: 3.1.5 The IRB/IEC may request more information than is outlined in paragraph 4.8.10 be given to subjects when, in
p.000009: the judgement of the IRB/IEC, the additional information would add meaningfully to the protection of the rights, safety
p.000009: and/or well-being of the subjects.
p.000009:
p.000009: 3.1.6 When a non-therapeutic trial is to be carried out with the consent of the subject’s legally acceptable
p.000009: representative (see 4.8.12, 4.8.14), the IRB/IEC should determine that the proposed protocol and/or
p.000009: other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements
p.000009: for such trials.
p.000009:
p.000009:
p.000009:
p.000010: 10
p.000010:
p.000010: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000010:
p.000010: 3.1.7 Where the protocol indicates that prior consent of the trial subject or the subject’s legally acceptable
p.000010: representative is not possible (see 4.8.15), the IRB/IEC should determine that the proposed protocol and/or other
p.000010: document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such
p.000010: trials (i.e., in emergency situations).
p.000010:
p.000010: 3.1.8 The IRB/IEC should review both the amount and method of payment to subjects to assure that
p.000010: neither presents problems of coercion or undue influence on the trial subjects. Payments to a subject should be
p.000010: prorated and not wholly contingent on completion of the trial by the subject.
p.000010:
p.000010: 3.1.9 The IRB/IEC should ensure that information regarding payment to subjects, including the methods, amounts, and
p.000010: schedule of payment to trial subjects, is set forth in the written informed consent form and any other written
p.000010: information to be provided to subjects. The way payment will be prorated should be specified.
p.000010:
p.000010: 3.2 Composition, Functions and Operations
p.000010:
p.000010: 3.2.1 The IRB/IEC should consist of a reasonable number of members, who collectively have the qualifications and
p.000010: experience to review and evaluate the science, medical aspects, and ethics of the proposed trial. It is recommended
p.000010: that the IRB/IEC should include:
p.000010:
p.000010: (a) At least five members.
p.000010:
p.000010: (b) At least one member whose primary area of interest is in a nonscientific area.
p.000010:
p.000010: (c) At least one member who is independent of the institution/trial site.
p.000010:
p.000010: Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial should vote/provide
p.000010: opinion on a trial-related matter.
p.000010:
p.000010: A list of IRB/IEC members and their qualifications should be maintained.
p.000010:
p.000010: 3.2.2 The IRB/IEC should perform its functions according to written operating procedures, should maintain
p.000010: written records of its activities and minutes of its meetings, and should comply with GCP and with the applicable
p.000010: regulatory requirement(s).
p.000010:
p.000010: 3.2.3 An IRB/IEC should make its decisions at announced meetings at which at least a quorum, as
p.000010: stipulated in its written operating procedures, is present.
p.000010:
p.000010: 3.2.4 Only members who participate in the IRB/IEC review and discussion should vote/provide
p.000010: their opinion and/or advise.
p.000010:
p.000010: 3.2.5 The investigator may provide information on any aspect of the trial, but should not participate
p.000010: in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC.
p.000010:
p.000010: 3.2.6 An IRB/IEC may invite nonmembers with expertise in special areas for assistance.
p.000010:
p.000010: 3.3 Procedures
p.000010: The IRB/IEC should establish, document in writing, and follow its procedures, which should include:
p.000010:
p.000010:
p.000011: 11
p.000011:
p.000011: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000011:
p.000011: 3.3.1 Determining its composition (names and qualifications of the members) and the authority under which it is
p.000011: established.
p.000011:
p.000011: 3.3.2 Scheduling, notifying its members of, and conducting its meetings.
p.000011:
p.000011: 3.3.3 Conducting initial and continuing review of trials.
p.000011:
p.000011: 3.3.4 Determining the frequency of continuing review, as appropriate.
p.000011:
p.000011: 3.3.5 Providing, according to the applicable regulatory requirements, expedited review and
p.000011: approval/favourable opinion of minor change(s) in ongoing trials that have the approval/favourable
p.000011: opinion of the IRB/IEC.
p.000011:
p.000011: 3.3.6 Specifying that no subject should be admitted to a trial before the IRB/IEC issues its written
p.000011: approval/favourable opinion of the trial.
p.000011:
p.000011: 3.3.7 Specifying that no deviations from, or changes of, the protocol should be initiated without
p.000011: prior written IRB/IEC approval/favourable opinion of an appropriate amendment, except when
p.000011: necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or
p.000011: administrative aspects of the trial (e.g., change of monitor(s), telephone number(s)) (see 4.5.2).
p.000011:
p.000011: 3.3.8 Specifying that the investigator should promptly report to the IRB/IEC:
p.000011: (a) Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial subjects (see 3.3.7,
p.000011: 4.5.2, 4.5.4).
p.000011: (b) Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial (see 4.10.2).
p.000011: (c) All adverse drug reactions (ADRs) that are both serious and unexpected.
p.000011: (d) New information that may affect adversely the safety of the subjects or the conduct of the trial.
p.000011:
p.000011: 3.3.9 Ensuring that the IRB/IEC promptly notify in writing the investigator/institution
p.000011: concerning:
p.000011: (a) Its trial-related decisions/opinions.
p.000011: (b) The reasons for its decisions/opinions.
p.000011: (c) Procedures for appeal of its decisions/opinions.
p.000011:
p.000011: 3.4 Records
p.000011: The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists, lists of
p.000011: occupations/affiliations of members, submitted documents, minutes of meetings, and correspondence) for
p.000011: a period of at least 3-years after completion of the trial and make them available upon request from the
p.000011: regulatory authority(ies).
p.000011: The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its written
...
p.000012: integrity of the trial-related duties and functions performed and any data generated.
p.000012:
p.000013: 13
p.000013:
p.000013: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000013:
p.000013: 4.3 Medical Care of Trial Subjects
p.000013:
p.000013: 4.3.1 A qualified physician (or dentist, when appropriate), who is an investigator or a sub-
p.000013: investigator for the trial, should be responsible for all trial-related medical (or dental) decisions.
p.000013:
p.000013: 4.3.2 During and following a subject's participation in a trial, the investigator/institution should ensure that
p.000013: adequate medical care is provided to a subject for any adverse events, including clinically
p.000013: significant laboratory values, related to the trial. The investigator/institution should
p.000013: inform a subject when medical care is needed for intercurrent illness(es) of which the investigator
p.000013: becomes aware.
p.000013:
p.000013: 4.3.3 It is recommended that the investigator inform the subject's primary physician about the subject's
p.000013: participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician
p.000013: being informed.
p.000013:
p.000013: 4.3.4 Although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the
p.000013: investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights.
p.000013:
p.000013: 4.4 Communication with IRB/IEC
p.000013:
p.000013: 4.4.1 Before initiating a trial, the investigator/institution should have written and dated
p.000013: approval/favourable opinion from the IRB/IEC for the trial protocol, written informed consent form,
p.000013: consent form updates, subject recruitment procedures (e.g., advertisements), and any other written
p.000013: information to be provided to subjects.
p.000013:
p.000013: 4.4.2 As part of the investigator's/institution’s written application to the IRB/IEC, the
p.000013: investigator/institution should provide the IRB/IEC with a current copy of the Investigator's
p.000013: Brochure. If the Investigator's Brochure is updated during the trial, the investigator/institution should
p.000013: supply a copy of the updated Investigator’s Brochure to the IRB/IEC.
p.000013:
p.000013: 4.4.3 During the trial the investigator/institution should provide to the IRB/IEC all documents subject to review.
p.000013:
p.000013: 4.5 Compliance with Protocol
p.000013:
p.000013: 4.5.1 The investigator/institution should conduct the trial in compliance with the protocol agreed to by
p.000013: the sponsor and, if required, by the regulatory authority(ies) and which was given approval/favourable opinion by the
p.000013: IRB/IEC. The investigator/institution and the sponsor should sign the protocol, or an alternative contract, to confirm
p.000013: agreement.
p.000013:
p.000013: 4.5.2 The investigator should not implement any deviation from, or changes of the protocol without
p.000013: agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of an
p.000013: amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s)
p.000013: involves only logistical or administrative aspects of the trial (e.g., change in monitor(s), change of
p.000013: telephone number(s)).
p.000013:
p.000013:
p.000013:
p.000013:
p.000014: 14
p.000014:
p.000014: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000014:
p.000014: 4.5.3 The investigator, or person designated by the investigator, should document and explain any deviation from the
p.000014: approved protocol.
p.000014:
p.000014: 4.5.4 The investigator may implement a deviation from, or a change of, the protocol to eliminate an
p.000014: immediate hazard(s) to trial subjects without prior IRB/IEC approval/favourable opinion. As soon
p.000014: as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed
p.000014: protocol amendment(s) should be submitted:
p.000014: (a) to the IRB/IEC for review and approval/favourable opinion,
p.000014: (b) to the sponsor for agreement and, if required,
p.000014: (c) to the regulatory authority(ies).
p.000014:
p.000014: 4.6 Investigational Product(s)
p.000014:
p.000014: 4.6.1 Responsibility for investigational product(s) accountability at the trial site(s) rests with the
p.000014: investigator/institution.
p.000014:
p.000014: 4.6.2 Where allowed/required, the investigator/institution may/should assign some or all of the
p.000014: investigator's/institution’s duties for investigational product(s) accountability at the trial site(s) to an
p.000014: appropriate pharmacist or another appropriate individual who is under the supervision of the
p.000014: investigator/institution..
p.000014:
p.000014: 4.6.3 The investigator/institution and/or a pharmacist or other appropriate individual, who is designated
p.000014: by the investigator/institution, should maintain records of the product's delivery to the trial site, the
p.000014: inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of
p.000014: unused product(s). These records should include dates, quantities, batch/serial numbers, expiration dates
p.000014: (if applicable), and the unique code numbers assigned to the investigational product(s) and trial
p.000014: subjects. Investigators should maintain records that document adequately that the subjects were provided the
p.000014: doses specified by the protocol and reconcile all investigational product(s) received from the sponsor.
p.000014:
p.000014: 4.6.4 The investigational product(s) should be stored as specified by the sponsor (see 5.13.2 and 5.14.3) and in
p.000014: accordance with applicable regulatory requirement(s).
p.000014:
p.000014: 4.6.5 The investigator should ensure that the investigational product(s) are used only in accordance with
p.000014: the approved protocol.
p.000014:
p.000014: 4.6.6 The investigator, or a person designated by the investigator/institution, should explain the correct use of
p.000014: the investigational product(s) to each subject and should check, at intervals appropriate for the trial, that each
p.000014: subject is following the instructions properly.
p.000014:
p.000014: 4.7 Randomization Procedures and Unblinding
p.000014: The investigator should follow the trial's randomization procedures, if any, and should ensure that the
p.000014: code is broken only in accordance with the protocol. If the trial is blinded, the investigator should
p.000014: promptly document and explain to the sponsor any premature unblinding (e.g., accidental unblinding,
p.000014: unblinding due to a serious adverse event) of the investigational product(s).
p.000014:
p.000014:
p.000014:
p.000015: 15
p.000015:
p.000015: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000015:
p.000015: 4.8 Informed Consent of Trial Subjects
p.000015:
p.000015: 4.8.1 In obtaining and documenting informed consent, the investigator should comply with the applicable regulatory
p.000015: requirement(s), and should adhere to GCP and to the ethical principles that have their origin in the
p.000015: Declaration of Helsinki. Prior to the beginning of the trial, the investigator should have the IRB/IEC's written
p.000015: approval/favourable opinion of the written informed consent form and any other written information to be provided to
p.000015: subjects.
p.000015:
p.000015: 4.8.2 The written informed consent form and any other written information to be provided to subjects should be
p.000015: revised whenever important new information becomes available that may be relevant to the subject’s consent. Any revised
p.000015: written informed consent form, and written information should receive the IRB/IEC's approval/favourable opinion in
p.000015: advance of use. The subject or the subject’s legally acceptable representative should be informed in a timely manner
p.000015: if new information becomes available that may be relevant to the subject’s willingness to continue
p.000015: participation in the trial. The communication of this information should be documented.
p.000015:
p.000015: 4.8.3 Neither the investigator, nor the trial staff, should coerce or unduly influence a subject to participate or
p.000015: to continue to participate in a trial.
p.000015:
p.000015: 4.8.4 None of the oral and written information concerning the trial, including the written informed
p.000015: consent form, should contain any language that causes the subject or the subject's legally acceptable
p.000015: representative to waive or to appear to waive any legal rights, or that releases or appears to release the
p.000015: investigator, the institution, the sponsor, or their agents from liability for negligence.
p.000015:
p.000015: 4.8.5 The investigator, or a person designated by the investigator, should fully inform the subject or,
p.000015: if the subject is unable to provide informed consent, the subject's legally acceptable representative, of
p.000015: all pertinent aspects of the trial including the written information and the approval/ favourable opinion by
p.000015: the IRB/IEC.
p.000015:
p.000015: 4.8.6 The language used in the oral and written information about the trial, including the written
p.000015: informed consent form, should be as non-technical as practical and should be understandable to the
p.000015: subject or the subject's legally acceptable representative and the impartial witness, where applicable.
p.000015:
p.000015: 4.8.7 Before informed consent may be obtained, the investigator, or a person designated by the investigator, should
p.000015: provide the subject or the subject's legally acceptable representative ample time and opportunity to inquire about
p.000015: details of the trial and to decide whether or not to participate in the trial. All questions about the trial
p.000015: should be answered to the satisfaction of the subject or the subject's legally acceptable representative.
p.000015:
p.000015: 4.8.8 Prior to a subject’s participation in the trial, the written informed consent form should be signed and
p.000015: personally dated by the subject or by the subject's legally acceptable representative, and by the person who
p.000015: conducted the informed consent discussion.
p.000015:
p.000015: 4.8.9 If a subject is unable to read or if a legally acceptable representative is unable to read, an impartial
p.000015: witness should be present during the entire informed consent discussion. After the written informed consent form and
...
p.000017: updates and a copy of any amendments to the written information provided to subjects.
p.000017:
p.000017: 4.8.12 When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only be enrolled in the
p.000017: trial with the consent of the subject’s legally acceptable representative (e.g., minors, or patients with
p.000017: severe dementia), the subject should be informed about the trial to the extent compatible with the subject’s
p.000017: understanding and, if capable, the subject should sign and personally date the written informed consent.
p.000017:
p.000017: 4.8.13 Except as described in 4.8.14, a non-therapeutic trial (i.e., a trial in which there is no
p.000017: anticipated direct clinical benefit to the subject), should be conducted in subjects who personally give
p.000017: consent and who sign and date the written informed consent form.
p.000017:
p.000017: 4.8.14 Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative
p.000017: provided the following conditions are fulfilled:
p.000017: (a) The objectives of the trial can not be met by means of a trial in subjects who can give informed consent
p.000017: personally.
p.000017: (b) The foreseeable risks to the subjects are low.
p.000017: (c) The negative impact on the subject’s well-being is minimized and low.
p.000017: (d) The trial is not prohibited by law.
p.000017: (e) The approval/favourable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and the
p.000017: written approval/ favourable opinion covers this aspect.
p.000017: Such trials, unless an exception is justified, should be conducted in patients having a disease or
p.000017: condition for which the investigational product is intended. Subjects in these trials should be particularly closely
p.000017: monitored and should be withdrawn if they appear to be unduly distressed.
p.000017:
p.000017: 4.8.15 In emergency situations, when prior consent of the subject is not possible, the consent of the subject's
p.000017: legally acceptable representative, if present, should be requested. When prior consent of the subject is
p.000017: not possible, and the subject’s legally acceptable representative is not available, enrolment of the
p.000017: subject should require measures described in the protocol and/or elsewhere, with documented
p.000017: approval/favourable opinion by the IRB/IEC, to protect the rights, safety and well-being of the subject and to ensure
p.000017: compliance with applicable regulatory requirements. The subject or the subject's legally acceptable representative
p.000017: should be informed about the trial as soon as possible
p.000017:
p.000017:
p.000017:
p.000018: 18
p.000018:
p.000018: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000018:
p.000018: and consent to continue and other consent as appropriate (see 4.8.10) should be requested.
p.000018:
p.000018: 4.9 Records and Reports ADDENDUM
p.000018: 4.9.0 The investigator/institution should maintain adequate and accurate source documents and trial records that
p.000018: include all pertinent observations on each of the site’s trial subjects. Source data should be
p.000018: attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data should be
p.000018: traceable, should not obscure the original entry, and should be explained if necessary (e.g., via an audit trail).
p.000018: 4.9.1 The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data reported to
p.000018: the sponsor in the CRFs and in all required reports.
p.000018:
p.000018: 4.9.2 Data reported on the CRF, that are derived from source documents, should be consistent with the source
p.000018: documents or the discrepancies should be explained.
p.000018:
p.000018: 4.9.3 Any change or correction to a CRF should be dated, initialed, and explained (if necessary) and
p.000018: should not obscure the original entry (i.e., an audit trail should be maintained); this applies to both
...
p.000019: evaluations should be reported to the sponsor according to the reporting requirements and within
p.000019: the time periods specified by the sponsor in the protocol.
p.000019:
p.000019: 4.11.3 For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any additional requested
p.000019: information (e.g., autopsy reports and terminal medical reports).
p.000019:
p.000019: 4.12 Premature Termination or Suspension of a Trial
p.000019: If the trial is prematurely terminated or suspended for any reason, the investigator/institution should
p.000019: promptly inform the trial subjects, should assure appropriate therapy and follow-up for the subjects, and, where
p.000019: required by the applicable regulatory requirement(s), should inform the regulatory authority(ies). In addition:
p.000019:
p.000019: 4.12.1 If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator
p.000019: should inform the institution where applicable, and the investigator/institution should promptly
p.000019: inform the sponsor and the IRB/IEC, and should provide the sponsor and the IRB/IEC a detailed written explanation of
p.000019: the termination or suspension.
p.000019:
p.000019: 4.12.2 If the sponsor terminates or suspends a trial (see 5.21), the investigator should promptly inform the
p.000019: institution where applicable and the investigator/institution should promptly inform the IRB/IEC and provide the
p.000019: IRB/IEC a detailed written explanation of the termination or suspension.
p.000019:
p.000019: 4.12.3 If the IRB/IEC terminates or suspends its approval/favourable opinion of a trial (see 3.1.2 and 3.3.9), the
p.000019: investigator should inform the institution where applicable and the investigator/institution should promptly
p.000019: notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension.
p.000019:
p.000019: 4.13 Final Report(s) by Investigator
p.000019: Upon completion of the trial, the investigator, where applicable, should inform the institution; the
p.000019: investigator/institution should provide the IRB/IEC with a summary of the trial’s outcome, and the regulatory
p.000019: authority(ies) with any reports required.
p.000019:
p.000019:
p.000019:
p.000020: 20
p.000020:
p.000020: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000020:
p.000020: 5. SPONSOR ADDENDUM
p.000020: 5.0 Quality Management
p.000020: The sponsor should implement a system to manage quality throughout all stages of the trial process.
p.000020: Sponsors should focus on trial activities essential to ensuring human subject protection and the reliability of trial
p.000020: results. Quality management includes the design of efficient clinical trial protocols and tools and
p.000020: procedures for data collection and processing, as well as the collection of information that is essential to decision
p.000020: making.
p.000020: The methods used to assure and control the quality of the trial should be proportionate to the risks inherent in
p.000020: the trial and the importance of the information collected. The sponsor should ensure that all aspects of the
p.000020: trial are operationally feasible and should avoid unnecessary complexity, procedures, and data collection.
...
p.000024: development of the investigational product. These documents should be retained for a longer period however if
p.000024: required by the applicable regulatory requirement(s) or if needed by the sponsor.
p.000024:
p.000024: 5.5.12 The sponsor should inform the investigator(s)/institution(s) in writing of the need for record
p.000024: retention and should notify the investigator(s)/institution(s) in writing when the trial related records are no
p.000024: longer needed.
p.000024:
p.000024: 5.6 Investigator Selection
p.000024:
p.000024: 5.6.1 The sponsor is responsible for selecting the investigator(s)/institution(s). Each investigator
p.000024: should be qualified by training and experience and should have adequate resources (see 4.1, 4.2) to properly
p.000024: conduct the trial for which the investigator is selected. If organization of a coordinating committee
p.000024: and/or selection of coordinating investigator(s) are to be utilized in multicentre trials, their organization
p.000024: and/or selection are the sponsor's responsibility.
p.000024:
p.000024: 5.6.2 Before entering an agreement with an investigator/institution to conduct a trial, the sponsor
p.000024: should provide the investigator(s)/institution(s) with the protocol and an up-to- date Investigator's Brochure,
p.000024: and should provide sufficient time for the investigator/institution to review the protocol and the
p.000024: information provided.
p.000024:
p.000024: 5.6.3 The sponsor should obtain the investigator's/institution's agreement:
p.000024: (a) to conduct the trial in compliance with GCP, with the applicable regulatory requirement(s)
p.000024: (see 4.1.3), and with the protocol agreed to by the sponsor and given approval/favourable opinion by the IRB/IEC (see
p.000024: 4.5.1);
p.000024: (b) to comply with procedures for data recording/reporting;
p.000024: (c) to permit monitoring, auditing and inspection (see 4.1.4) and
p.000024: (d) to retain the trial related essential documents until the sponsor informs the
p.000024: investigator/institution these documents are no longer needed (see 4.9.4 and 5.5.12).
p.000024: The sponsor and the investigator/institution should sign the protocol, or an alternative document, to
p.000024: confirm this agreement.
p.000024:
p.000024: 5.7 Allocation of Responsibilities
p.000024: Prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related duties and functions.
p.000024:
p.000024: 5.8 Compensation to Subjects and Investigators
p.000024:
p.000024: 5.8.1 If required by the applicable regulatory requirement(s), the sponsor should provide insurance or
p.000024: should indemnify (legal and financial coverage) the investigator/the institution against claims
p.000024: arising from the trial, except for claims that arise from malpractice and/or negligence.
p.000024:
p.000024:
p.000024:
p.000024:
p.000025: 25
p.000025:
p.000025: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000025:
p.000025: 5.8.2 The sponsor's policies and procedures should address the costs of treatment of trial subjects in
p.000025: the event of trial-related injuries in accordance with the applicable regulatory requirement(s).
p.000025:
p.000025: 5.8.3 When trial subjects receive compensation, the method and manner of compensation should comply with
p.000025: applicable regulatory requirement(s).
p.000025:
p.000025: 5.9 Financing
p.000025: The financial aspects of the trial should be documented in an agreement between the sponsor and the
p.000025: investigator/institution.
p.000025:
p.000025: 5.10 Notification/Submission to Regulatory Authority(ies)
p.000025: Before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator, if required by the
p.000025: applicable regulatory requirement(s)) should submit any required application(s) to the appropriate
p.000025: authority(ies) for review, acceptance, and/or permission (as required by the applicable regulatory
p.000025: requirement(s)) to begin the trial(s). Any notification/submission should be dated and contain sufficient information
p.000025: to identify the protocol.
p.000025:
p.000025: 5.11 Confirmation of Review by IRB/IEC
p.000025:
p.000025: 5.11.1 The sponsor should obtain from the investigator/institution:
p.000025: (a) The name and address of the investigator's/institution’s IRB/IEC.
p.000025: (b) A statement obtained from the IRB/IEC that it is organized and operates according to GCP and the applicable laws
p.000025: and regulations.
p.000025: (c) Documented IRB/IEC approval/favourable opinion and, if requested by the sponsor, a current copy of protocol,
p.000025: written informed consent form(s) and any other written information to be provided to subjects, subject recruiting
p.000025: procedures, and documents related to payments and compensation available to the subjects, and any other
p.000025: documents that the IRB/IEC may have requested.
p.000025:
p.000025: 5.11.2 If the IRB/IEC conditions its approval/favourable opinion upon change(s) in any aspect of the trial, such as
p.000025: modification(s) of the protocol, written informed consent form and any other written information to be provided
p.000025: to subjects, and/or other procedures, the sponsor should obtain from the investigator/institution a copy
p.000025: of the modification(s) made and the date approval/favourable opinion was given by the IRB/IEC.
p.000025:
p.000025: 5.11.3 The sponsor should obtain from the investigator/institution documentation and dates of any IRB/IEC
p.000025: reapprovals/re-evaluations with favourable opinion, and of any withdrawals or suspensions of approval/favourable
p.000025: opinion.
p.000025:
p.000025: 5.12 Information on Investigational Product(s)
p.000025:
p.000025: 5.12.1 When planning trials, the sponsor should ensure that sufficient safety and efficacy data from nonclinical
p.000025: studies and/or clinical trials are available to support human exposure by the route, at the dosages, for the duration,
p.000025: and in the trial population to be studied.
p.000025:
p.000025: 5.12.2 The sponsor should update the Investigator's Brochure as significant new information becomes
p.000025: available (see 7. Investigator's Brochure).
p.000025:
p.000025:
p.000026: 26
p.000026:
p.000026: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000026:
p.000026: 5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s)
p.000026:
p.000026: 5.13.1 The sponsor should ensure that the investigational product(s) (including active comparator(s)
p.000026: and placebo, if applicable) is characterized as appropriate to the stage of development of the product(s), is
p.000026: manufactured in accordance with any applicable GMP, and is coded and labelled in a manner that protects the blinding,
p.000026: if applicable. In addition, the labelling should comply with applicable regulatory requirement(s).
p.000026:
p.000026: 5.13.2 The sponsor should determine, for the investigational product(s), acceptable storage temperatures,
p.000026: storage conditions (e.g., protection from light), storage times, reconstitution fluids and
p.000026: procedures, and devices for product infusion, if any. The sponsor should inform all involved parties
p.000026: (e.g., monitors, investigators, pharmacists, storage managers) of these determinations.
p.000026:
p.000026: 5.13.3 The investigational product(s) should be packaged to prevent contamination and unacceptable
p.000026: deterioration during transport and storage.
p.000026:
p.000026: 5.13.4 In blinded trials, the coding system for the investigational product(s) should include a mechanism
p.000026: that permits rapid identification of the product(s) in case of a medical emergency, but does not permit
p.000026: undetectable breaks of the blinding.
p.000026:
p.000026: 5.13.5 If significant formulation changes are made in the investigational or comparator product(s)
p.000026: during the course of clinical development, the results of any additional studies of the formulated product(s)
p.000026: (e.g., stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly
p.000026: alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in
p.000026: clinical trials.
p.000026:
p.000026: 5.14 Supplying and Handling Investigational Product(s)
p.000026:
p.000026: 5.14.1 The sponsor is responsible for supplying the investigator(s)/institution(s) with the investigational
p.000026: product(s).
p.000026:
p.000026: 5.14.2 The sponsor should not supply an investigator/institution with the investigational product(s)
p.000026: until the sponsor obtains all required documentation (e.g., approval/favourable opinion from IRB/IEC and regulatory
p.000026: authority(ies)).
p.000026:
p.000026: 5.14.3 The sponsor should ensure that written procedures include instructions that the
p.000026: investigator/institution should follow for the handling and storage of investigational product(s) for the
p.000026: trial and documentation thereof. The procedures should address adequate and safe receipt, handling, storage,
p.000026: dispensing, retrieval of unused product from subjects, and return of unused investigational product(s) to the
p.000026: sponsor (or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory
p.000026: requirement(s)).
p.000026:
p.000026: 5.14.4 The sponsor should:
p.000026: (a) Ensure timely delivery of investigational product(s) to the investigator(s).
p.000026: (b) Maintain records that document shipment, receipt, disposition, return, and destruction of the
p.000026: investigational product(s) (see 8. Essential Documents for the Conduct of a Clinical Trial).
p.000026:
p.000026:
p.000026:
p.000027: 27
p.000027:
p.000027: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000027:
p.000027: (c) Maintain a system for retrieving investigational products and documenting this retrieval (e.g., for
p.000027: deficient product recall, reclaim after trial completion, expired product reclaim).
p.000027: (d) Maintain a system for the disposition of unused investigational product(s) and for the documentation of this
p.000027: disposition.
p.000027:
p.000027: 5.14.5 The sponsor should:
p.000027: (a) Take steps to ensure that the investigational product(s) are stable over the period of use.
p.000027: (b) Maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm
p.000027: specifications, should this become necessary, and maintain records of batch sample analyses and
p.000027: characteristics. To the extent stability permits, samples should be retained either until the analyses of
p.000027: the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the
p.000027: longer retention period.
p.000027:
p.000027: 5.15 Record Access
p.000027:
p.000027: 5.15.1 The sponsor should ensure that it is specified in the protocol or other written agreement that the
p.000027: investigator(s)/institution(s) provide direct access to source data/documents for trial-related monitoring, audits,
p.000027: IRB/IEC review, and regulatory inspection.
p.000027:
p.000027: 5.15.2 The sponsor should verify that each subject has consented, in writing, to direct access to his/her original
p.000027: medical records for trial-related monitoring, audit, IRB/IEC review, and regulatory inspection.
p.000027:
p.000027: 5.16 Safety Information
p.000027:
p.000027: 5.16.1 The sponsor is responsible for the ongoing safety evaluation of the investigational product(s).
p.000027:
p.000027: 5.16.2 The sponsor should promptly notify all concerned investigator(s)/institution(s) and the regulatory
p.000027: authority(ies) of findings that could affect adversely the safety of subjects, impact the conduct of the
p.000027: trial, or alter the IRB/IEC's approval/favourable opinion to continue the trial.
p.000027:
p.000027: 5.17 Adverse Drug Reaction Reporting
p.000027:
p.000027: 5.17.1 The sponsor should expedite the reporting to all concerned investigator(s)/institutions(s), to the
p.000027: IRB(s)/IEC(s), where required, and to the regulatory authority(ies) of all adverse drug reactions (ADRs) that are both
p.000027: serious and unexpected.
p.000027:
p.000027: 5.17.2 Such expedited reports should comply with the applicable regulatory requirement(s) and with the ICH Guideline
p.000027: for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.
p.000027:
p.000027: 5.17.3 The sponsor should submit to the regulatory authority(ies) all safety updates and periodic reports, as required
p.000027: by applicable regulatory requirement(s).
p.000027:
p.000027:
p.000027:
p.000028: 28
p.000028:
p.000028: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000028:
p.000028:
p.000028: 5.18 Monitoring
p.000028:
p.000028: 5.18.1 Purpose
p.000028: The purposes of trial monitoring are to verify that:
p.000028: (a) The rights and well-being of human subjects are protected.
p.000028: (b) The reported trial data are accurate, complete, and verifiable from source documents.
p.000028: (c) The conduct of the trial is in compliance with the currently approved
p.000028: protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).
p.000028:
p.000028: 5.18.2 Selection and Qualifications of Monitors
p.000028: (a) Monitors should be appointed by the sponsor.
...
p.000032: If a trial is prematurely terminated or suspended, the sponsor should promptly inform the
p.000032: investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the reason(s) for
p.000032: the termination or suspension. The IRB/IEC should also be informed promptly and provided the reason(s) for the
p.000032: termination or suspension by the sponsor or by the investigator/institution, as specified by the applicable
p.000032: regulatory requirement(s).
p.000032:
p.000032: 5.22 Clinical Trial/Study Reports
p.000032: Whether the trial is completed or prematurely terminated, the sponsor should ensure that the clinical
p.000032: trial reports are prepared and provided to the regulatory agency(ies) as required by the applicable regulatory
p.000032: requirement(s). The sponsor should also ensure that the clinical trial reports in marketing applications meet the
p.000032: standards of the ICH Guideline for Structure and Content of
p.000032:
p.000032:
p.000032:
p.000033: 33
p.000033:
p.000033: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000033:
p.000033: Clinical Study Reports. (NOTE: The ICH Guideline for Structure and Content of Clinical Study Reports specifies that
p.000033: abbreviated study reports may be acceptable in certain cases.)
p.000033:
p.000033: 5.23 Multicentre Trials
p.000033: For multicentre trials, the sponsor should ensure that:
p.000033:
p.000033: 5.23.1 All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor and, if
p.000033: required, by the regulatory authority(ies), and given approval/favourable opinion by the IRB/IEC.
p.000033:
p.000033: 5.23.2 The CRFs are designed to capture the required data at all multicentre trial sites. For those investigators who
p.000033: are collecting additional data, supplemental CRFs should also be provided that are designed to capture the
p.000033: additional data.
p.000033:
p.000033: 5.23.3 The responsibilities of coordinating investigator(s) and the other participating investigators
p.000033: are documented prior to the start of the trial.
p.000033:
p.000033: 5.23.4 All investigators are given instructions on following the protocol, on complying with a uniform set of
p.000033: standards for the assessment of clinical and laboratory findings, and on completing the CRFs.
p.000033:
p.000033: 5.23.5 Communication between investigators is facilitated.
p.000033:
p.000033: 6. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S)
p.000033: The contents of a trial protocol should generally include the following topics. However, site specific
p.000033: information may be provided on separate protocol page(s), or addressed in a separate agreement, and some of the
p.000033: information listed below may be contained in other protocol referenced documents, such as an Investigator’s
p.000033: Brochure.
p.000033:
p.000033: 6.1 General Information
p.000033:
p.000033: 6.1.1 Protocol title, protocol identifying number, and date. Any amendment(s) should also bear the amendment
p.000033: number(s) and date(s).
p.000033:
p.000033: 6.1.2 Name and address of the sponsor and monitor (if other than the sponsor).
p.000033:
p.000033: 6.1.3 Name and title of the person(s) authorized to sign the protocol and the protocol amendment(s) for
p.000033: the sponsor.
p.000033:
p.000033: 6.1.4 Name, title, address, and telephone number(s) of the sponsor's medical expert (or dentist when appropriate)
...
p.000046:
p.000046:
p.000046:
p.000046: 8.2.4
p.000046:
p.000046:
p.000046: - ADVERTISEMENT FOR SUBJECT
p.000046: RECRUITMENT (if used)
p.000046:
p.000046: FINANCIAL ASPECTS OF THE TRIAL
p.000046:
p.000046:
p.000046: To document that recruitment measures are appropriate and not coercive
p.000046:
p.000046: To document the financial agreement between the investigator/institution and the sponsor for the trial
p.000046: Investigator/ Institution
p.000046: X X
p.000046: Sponsor
p.000046:
p.000046:
p.000046:
p.000046:
p.000046: X
p.000046:
p.000046:
p.000046: 8.2.5
p.000046:
p.000046: 8.2.6
p.000046: INSURANCE STATEMENT
p.000046: (where required)
p.000046:
p.000046: SIGNED AGREEMENT BETWEEN INVOLVED PARTIES, e.g.:
p.000046: - investigator/institution and sponsor
p.000046: - investigator/institution and CRO
p.000046: - sponsor and CRO
p.000046: - investigator/institution and authority(ies) (where required)
p.000046: To document that compensation to subject(s) for X trial-related injury will be available
p.000046:
p.000046: To document agreements
p.000046:
p.000046: X X
p.000046:
p.000046:
p.000046: X
p.000046: X
p.000046:
p.000046:
p.000046:
p.000046: X X
p.000046: (where required)
p.000046: X X
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000047: 47
p.000047:
p.000047: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000047:
p.000047:
p.000047: Title of Document
p.000047: Purpose
p.000047: Located in Files of
p.000047:
p.000047:
p.000047:
p.000047: 8.2.7
p.000047:
p.000047:
p.000047: DATED, DOCUMENTED APPROVAL/FAVOURABLE OPINION OF INSTITUTIONAL REVIEW BOARD (IRB)
p.000047: /INDEPENDENT ETHICS COMMITTEE (IEC) OF THE FOLLOWING:
p.000047: - protocol and any amendments
p.000047: - CRF (if applicable)
p.000047: - informed consent form(s)
p.000047: - any other written information to be provided to the subject(s)
p.000047: - advertisement for subject recruitment (if used)
p.000047: - subject compensation (if any)
p.000047: - any other documents given approval/ favourable opinion
p.000047:
p.000047:
p.000047: To document that the trial has been subject to IRB/IEC review and given approval/favourable opinion. To
p.000047: identify the version number and date of the document(s)
p.000047: Investigator/ Institution
p.000047: X
p.000047: Sponsor
p.000047:
p.000047: X
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000048: 48
p.000048:
p.000048: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000048:
p.000048:
p.000048:
p.000048:
p.000048: Title of Document
p.000048: Purpose
p.000048: Located in Files of
p.000048:
p.000048:
p.000048:
p.000048: 8.2.8
p.000048:
p.000048:
p.000048:
p.000048: 8.2.9
p.000048:
p.000048:
p.000048:
p.000048:
p.000048: 8.2.10
p.000048:
p.000048:
p.000048:
p.000048: 8.2.11
p.000048:
p.000048:
p.000048: INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE COMPOSITION
p.000048:
p.000048: REGULATORY AUTHORITY(IES) AUTHORISATION/APPROVAL/ NOTIFICATION OF PROTOCOL
p.000048: (where required)
p.000048:
p.000048:
p.000048: CURRICULUM VITAE AND/OR OTHER RELEVANT DOCUMENTS EVIDENCING QUALIFICATIONS OF INVESTIGATOR(S) AND SUB-INVESTIGATOR(S)
p.000048:
p.000048: NORMAL VALUE(S)/RANGE(S) FOR MEDICAL/ LABORATORY/TECHNICAL PROCEDURE(S) AND/OR TEST(S) INCLUDED IN THE PROTOCOL
p.000048:
p.000048:
p.000048: To document that the IRB/IEC is constituted in agreement with GCP
p.000048:
p.000048:
p.000048: To document appropriate authorisation/approval/notification by the regulatory authority(ies) has been obtained prior to
p.000048: initiation of the trial in compliance with the applicable regulatory requirement(s)
p.000048:
...
p.000052: evidence that all new relevant information is documented as it becomes available
p.000052:
p.000052:
p.000052:
p.000052: Title of Document
p.000052: Purpose
p.000052: Located in Files of
p.000052:
p.000052:
p.000052:
p.000052: 8.3.1
p.000052:
p.000052:
p.000052: 8.3.2
p.000052:
p.000052:
p.000052: INVESTIGATOR’S BROCHURE UPDATES
p.000052:
p.000052:
p.000052: ANY REVISION TO:
p.000052: - protocol/amendment(s) and CRF
p.000052: - informed consent form
p.000052: - any other written information provided to subjects
p.000052: - advertisement for subject recruitment (if used)
p.000052:
p.000052:
p.000052: To document that investigator is informed in a timely manner of relevant information as it becomes
p.000052: available
p.000052:
p.000052: To document revisions of these trial related documents that take effect during trial
p.000052: Investigator/ Institution
p.000052: X
p.000052:
p.000052:
p.000052: X
p.000052: Sponsor
p.000052:
p.000052: X
p.000052:
p.000052:
p.000052: X
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000053: 53
p.000053:
p.000053: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000053:
p.000053:
p.000053: Title of Document
p.000053: Purpose
p.000053: Located in Files of
p.000053:
p.000053:
p.000053:
p.000053: 8.3.3
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053: 8.3.4
p.000053:
p.000053:
p.000053:
p.000053: 8.3.5
p.000053:
p.000053:
p.000053: DATED, DOCUMENTED APPROVAL/FAVOURABLE OPINION OF INSTITUTIONAL REVIEW BOARD (IRB)
p.000053: /INDEPENDENT ETHICS COMMITTEE (IEC) OF THE FOLLOWING:
p.000053: - protocol amendment(s)
p.000053: - revision(s) of:
p.000053: - informed consent form
p.000053: - any other written information to be provided to the subject
p.000053: - advertisement for subject recruitment (if used)
p.000053: - any other documents given approval/favourable opinion
p.000053: - continuing review of trial (where required)
p.000053: REGULATORY AUTHORITY(IES) AUTHORISATIONS/APPROVALS/NOTIFIC ATIONS WHERE REQUIRED FOR:
p.000053: - protocol amendment(s) and other documents
p.000053: CURRICULUM VITAE FOR NEW INVESTIGATOR(S) AND/OR SUB- INVESTIGATOR(S)
p.000053:
p.000053:
p.000053: To document that the amendment(s) and/or revision(s) have been subject to IRB/IEC review and were
p.000053: given approval/favourable opinion. To identify the version number and date of the document(s).
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053: To document compliance with applicable regulatory requirements
p.000053:
p.000053:
p.000053: (see 8.2.10)
p.000053: Investigator/ Institution
p.000053: X
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053: X
p.000053: (where required)
p.000053:
p.000053: X
p.000053: Sponsor
p.000053:
p.000053: X
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053: X
p.000053:
p.000053:
p.000053:
p.000053: X
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000054: 54
p.000054:
p.000054: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000054:
p.000054:
p.000054: Title of Document
p.000054: Purpose
p.000054: Located in Files of
p.000054:
p.000054:
p.000054:
p.000054: 8.3.6
p.000054:
p.000054:
p.000054:
p.000054:
p.000054: 8.3.7
p.000054:
p.000054:
p.000054:
p.000054:
p.000054:
p.000054:
p.000054: 8.3.8
p.000054:
p.000054:
p.000054: 8.3.9
p.000054:
p.000054:
p.000054: 8.3.10
p.000054:
p.000054:
p.000054: UPDATES TO NORMAL VALUE(S)/RANGE(S) FOR MEDICAL/ LABORATORY/ TECHNICAL PROCEDURE(S)/TEST(S) INCLUDED IN THE PROTOCOL
p.000054:
p.000054: UPDATES OF MEDICAL/LABORATORY/ TECHNICAL PROCEDURES/TESTS
p.000054: - certification or
p.000054: - accreditation or
p.000054: - established quality control and/or external quality assessment or
p.000054: - other validation (where required)
p.000054: DOCUMENTATION OF INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALS SHIPMENT
...
General/Other / Incapacitated
Searching for indicator incapacity:
(return to top)
p.000005: 1.46 Quality Assurance (QA)
p.000005: All those planned and systematic actions that are established to ensure that the trial is performed and the data are
p.000005: generated, documented (recorded), and reported in compliance with Good Clinical Practice (GCP) and the
p.000005: applicable regulatory requirement(s).
p.000005: 1.47 Quality Control (QC)
p.000005: The operational techniques and activities undertaken within the quality assurance system to verify that the
p.000005: requirements for quality of the trial-related activities have been fulfilled.
p.000005: 1.48 Randomization
p.000005: The process of assigning trial subjects to treatment or control groups using an element of chance to determine the
p.000005: assignments in order to reduce bias.
p.000005: 1.49 Regulatory Authorities
p.000005: Bodies having the power to regulate. In the ICH GCP Guideline the expression Regulatory Authorities
p.000005: includes the authorities that review submitted clinical data and those that conduct inspections (see 1.29).
p.000005: These bodies are sometimes referred to as competent authorities.
p.000005:
p.000005:
p.000005:
p.000005:
p.000006: 6
p.000006:
p.000006: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000006:
p.000006: 1.50 Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)
p.000006: Any untoward medical occurrence that at any dose:
p.000006: - results in death,
p.000006: - is life-threatening,
p.000006: - requires inpatient hospitalization or prolongation of existing hospitalization,
p.000006: - results in persistent or significant disability/incapacity, or
p.000006: - is a congenital anomaly/birth defect
p.000006: (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for Expedited
p.000006: Reporting).
p.000006: 1.51 Source Data
p.000006: All information in original records and certified copies of original records of clinical findings, observations, or
p.000006: other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are
p.000006: contained in source documents (original records or certified copies).
p.000006: 1.52 Source Documents
p.000006: Original documents, data, and records (e.g., hospital records, clinical and office charts,
p.000006: laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing records,
p.000006: recorded data from automated instruments, copies or transcriptions certified after verification as being
p.000006: accurate copies, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject files,
p.000006: and records kept at the pharmacy, at the laboratories and at medico-technical departments involved in the clinical
p.000006: trial).
p.000006: 1.53 Sponsor
p.000006: An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or
p.000006: financing of a clinical trial.
p.000006: 1.54 Sponsor-Investigator
p.000006: An individual who both initiates and conducts, alone or with others, a clinical trial, and under whose immediate
p.000006: direction the investigational product is administered to, dispensed to, or used by a subject. The term does not
p.000006: include any person other than an individual (e.g., it does not include a corporation or an agency). The
...
General/Other / Natural Hazards
Searching for indicator hazard:
(return to top)
p.000013: consent form updates, subject recruitment procedures (e.g., advertisements), and any other written
p.000013: information to be provided to subjects.
p.000013:
p.000013: 4.4.2 As part of the investigator's/institution’s written application to the IRB/IEC, the
p.000013: investigator/institution should provide the IRB/IEC with a current copy of the Investigator's
p.000013: Brochure. If the Investigator's Brochure is updated during the trial, the investigator/institution should
p.000013: supply a copy of the updated Investigator’s Brochure to the IRB/IEC.
p.000013:
p.000013: 4.4.3 During the trial the investigator/institution should provide to the IRB/IEC all documents subject to review.
p.000013:
p.000013: 4.5 Compliance with Protocol
p.000013:
p.000013: 4.5.1 The investigator/institution should conduct the trial in compliance with the protocol agreed to by
p.000013: the sponsor and, if required, by the regulatory authority(ies) and which was given approval/favourable opinion by the
p.000013: IRB/IEC. The investigator/institution and the sponsor should sign the protocol, or an alternative contract, to confirm
p.000013: agreement.
p.000013:
p.000013: 4.5.2 The investigator should not implement any deviation from, or changes of the protocol without
p.000013: agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of an
p.000013: amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s)
p.000013: involves only logistical or administrative aspects of the trial (e.g., change in monitor(s), change of
p.000013: telephone number(s)).
p.000013:
p.000013:
p.000013:
p.000013:
p.000014: 14
p.000014:
p.000014: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000014:
p.000014: 4.5.3 The investigator, or person designated by the investigator, should document and explain any deviation from the
p.000014: approved protocol.
p.000014:
p.000014: 4.5.4 The investigator may implement a deviation from, or a change of, the protocol to eliminate an
p.000014: immediate hazard(s) to trial subjects without prior IRB/IEC approval/favourable opinion. As soon
p.000014: as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed
p.000014: protocol amendment(s) should be submitted:
p.000014: (a) to the IRB/IEC for review and approval/favourable opinion,
p.000014: (b) to the sponsor for agreement and, if required,
p.000014: (c) to the regulatory authority(ies).
p.000014:
p.000014: 4.6 Investigational Product(s)
p.000014:
p.000014: 4.6.1 Responsibility for investigational product(s) accountability at the trial site(s) rests with the
p.000014: investigator/institution.
p.000014:
p.000014: 4.6.2 Where allowed/required, the investigator/institution may/should assign some or all of the
p.000014: investigator's/institution’s duties for investigational product(s) accountability at the trial site(s) to an
p.000014: appropriate pharmacist or another appropriate individual who is under the supervision of the
p.000014: investigator/institution..
p.000014:
p.000014: 4.6.3 The investigator/institution and/or a pharmacist or other appropriate individual, who is designated
p.000014: by the investigator/institution, should maintain records of the product's delivery to the trial site, the
p.000014: inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of
p.000014: unused product(s). These records should include dates, quantities, batch/serial numbers, expiration dates
p.000014: (if applicable), and the unique code numbers assigned to the investigational product(s) and trial
...
General/Other / Public Emergency
Searching for indicator emergency:
(return to top)
p.000007: related data.
p.000007: 1.59 Trial Site
p.000007: The location(s) where trial-related activities are actually conducted.
p.000007: 1.60 Unexpected Adverse Drug Reaction
p.000007: An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g.,
p.000007: Investigator's Brochure for an unapproved investigational product or package insert/summary of product characteristics
p.000007: for an approved product) (see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for
p.000007: Expedited Reporting).
p.000007:
p.000007: 1.61 Vulnerable Subjects
p.000007: Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether
p.000007: justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a
p.000007: hierarchy in case of refusal to participate. Examples are members of a group with a hierarchical structure,
p.000007: such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees
p.000007: of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable
p.000007: subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons,
p.000007: patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and
p.000007: those incapable of giving consent.
p.000007: 1.62 Well-being (of the trial subjects)
p.000007: The physical and mental integrity of the subjects participating in a clinical trial.
p.000007: ADDENDUM
p.000007: 1.63 Certified Copy
p.000007: A copy (irrespective of the type of media used) of the original record that has been verified (i.e., by a dated
p.000007: signature or by generation through a validated process) to have the same information, including data that describe the
p.000007: context, content, and structure, as the original.
p.000007: 1.64 Monitoring Plan
p.000007: A document that describes the strategy, methods, responsibilities, and requirements for monitoring
p.000007: the trial.
p.000007: 1.65 Validation of Computerized Systems
p.000007: A process of establishing and documenting that the specified requirements of a computerized system can be
p.000007: consistently fulfilled from design until decommissioning of the system or transition to a new system. The
p.000007: approach to validation should be based on a risk assessment that takes into consideration the intended use of the
p.000007: system and the potential of the system to affect human subject protection and reliability of trial results.
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
p.000007:
...
p.000009: current curriculum vitae and/or by any other relevant documentation the IRB/IEC requests.
p.000009:
p.000009: 3.1.4 The IRB/IEC should conduct continuing review of each ongoing trial at intervals appropriate to the
p.000009: degree of risk to human subjects, but at least once per year.
p.000009:
p.000009: 3.1.5 The IRB/IEC may request more information than is outlined in paragraph 4.8.10 be given to subjects when, in
p.000009: the judgement of the IRB/IEC, the additional information would add meaningfully to the protection of the rights, safety
p.000009: and/or well-being of the subjects.
p.000009:
p.000009: 3.1.6 When a non-therapeutic trial is to be carried out with the consent of the subject’s legally acceptable
p.000009: representative (see 4.8.12, 4.8.14), the IRB/IEC should determine that the proposed protocol and/or
p.000009: other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements
p.000009: for such trials.
p.000009:
p.000009:
p.000009:
p.000010: 10
p.000010:
p.000010: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000010:
p.000010: 3.1.7 Where the protocol indicates that prior consent of the trial subject or the subject’s legally acceptable
p.000010: representative is not possible (see 4.8.15), the IRB/IEC should determine that the proposed protocol and/or other
p.000010: document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such
p.000010: trials (i.e., in emergency situations).
p.000010:
p.000010: 3.1.8 The IRB/IEC should review both the amount and method of payment to subjects to assure that
p.000010: neither presents problems of coercion or undue influence on the trial subjects. Payments to a subject should be
p.000010: prorated and not wholly contingent on completion of the trial by the subject.
p.000010:
p.000010: 3.1.9 The IRB/IEC should ensure that information regarding payment to subjects, including the methods, amounts, and
p.000010: schedule of payment to trial subjects, is set forth in the written informed consent form and any other written
p.000010: information to be provided to subjects. The way payment will be prorated should be specified.
p.000010:
p.000010: 3.2 Composition, Functions and Operations
p.000010:
p.000010: 3.2.1 The IRB/IEC should consist of a reasonable number of members, who collectively have the qualifications and
p.000010: experience to review and evaluate the science, medical aspects, and ethics of the proposed trial. It is recommended
p.000010: that the IRB/IEC should include:
p.000010:
p.000010: (a) At least five members.
p.000010:
p.000010: (b) At least one member whose primary area of interest is in a nonscientific area.
p.000010:
p.000010: (c) At least one member who is independent of the institution/trial site.
p.000010:
p.000010: Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial should vote/provide
p.000010: opinion on a trial-related matter.
p.000010:
p.000010: A list of IRB/IEC members and their qualifications should be maintained.
p.000010:
...
p.000017:
p.000017: 4.8.13 Except as described in 4.8.14, a non-therapeutic trial (i.e., a trial in which there is no
p.000017: anticipated direct clinical benefit to the subject), should be conducted in subjects who personally give
p.000017: consent and who sign and date the written informed consent form.
p.000017:
p.000017: 4.8.14 Non-therapeutic trials may be conducted in subjects with consent of a legally acceptable representative
p.000017: provided the following conditions are fulfilled:
p.000017: (a) The objectives of the trial can not be met by means of a trial in subjects who can give informed consent
p.000017: personally.
p.000017: (b) The foreseeable risks to the subjects are low.
p.000017: (c) The negative impact on the subject’s well-being is minimized and low.
p.000017: (d) The trial is not prohibited by law.
p.000017: (e) The approval/favourable opinion of the IRB/IEC is expressly sought on the inclusion of such subjects, and the
p.000017: written approval/ favourable opinion covers this aspect.
p.000017: Such trials, unless an exception is justified, should be conducted in patients having a disease or
p.000017: condition for which the investigational product is intended. Subjects in these trials should be particularly closely
p.000017: monitored and should be withdrawn if they appear to be unduly distressed.
p.000017:
p.000017: 4.8.15 In emergency situations, when prior consent of the subject is not possible, the consent of the subject's
p.000017: legally acceptable representative, if present, should be requested. When prior consent of the subject is
p.000017: not possible, and the subject’s legally acceptable representative is not available, enrolment of the
p.000017: subject should require measures described in the protocol and/or elsewhere, with documented
p.000017: approval/favourable opinion by the IRB/IEC, to protect the rights, safety and well-being of the subject and to ensure
p.000017: compliance with applicable regulatory requirements. The subject or the subject's legally acceptable representative
p.000017: should be informed about the trial as soon as possible
p.000017:
p.000017:
p.000017:
p.000018: 18
p.000018:
p.000018: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000018:
p.000018: and consent to continue and other consent as appropriate (see 4.8.10) should be requested.
p.000018:
p.000018: 4.9 Records and Reports ADDENDUM
p.000018: 4.9.0 The investigator/institution should maintain adequate and accurate source documents and trial records that
p.000018: include all pertinent observations on each of the site’s trial subjects. Source data should be
p.000018: attributable, legible, contemporaneous, original, accurate, and complete. Changes to source data should be
...
p.000025: available (see 7. Investigator's Brochure).
p.000025:
p.000025:
p.000026: 26
p.000026:
p.000026: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000026:
p.000026: 5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s)
p.000026:
p.000026: 5.13.1 The sponsor should ensure that the investigational product(s) (including active comparator(s)
p.000026: and placebo, if applicable) is characterized as appropriate to the stage of development of the product(s), is
p.000026: manufactured in accordance with any applicable GMP, and is coded and labelled in a manner that protects the blinding,
p.000026: if applicable. In addition, the labelling should comply with applicable regulatory requirement(s).
p.000026:
p.000026: 5.13.2 The sponsor should determine, for the investigational product(s), acceptable storage temperatures,
p.000026: storage conditions (e.g., protection from light), storage times, reconstitution fluids and
p.000026: procedures, and devices for product infusion, if any. The sponsor should inform all involved parties
p.000026: (e.g., monitors, investigators, pharmacists, storage managers) of these determinations.
p.000026:
p.000026: 5.13.3 The investigational product(s) should be packaged to prevent contamination and unacceptable
p.000026: deterioration during transport and storage.
p.000026:
p.000026: 5.13.4 In blinded trials, the coding system for the investigational product(s) should include a mechanism
p.000026: that permits rapid identification of the product(s) in case of a medical emergency, but does not permit
p.000026: undetectable breaks of the blinding.
p.000026:
p.000026: 5.13.5 If significant formulation changes are made in the investigational or comparator product(s)
p.000026: during the course of clinical development, the results of any additional studies of the formulated product(s)
p.000026: (e.g., stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly
p.000026: alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in
p.000026: clinical trials.
p.000026:
p.000026: 5.14 Supplying and Handling Investigational Product(s)
p.000026:
p.000026: 5.14.1 The sponsor is responsible for supplying the investigator(s)/institution(s) with the investigational
p.000026: product(s).
p.000026:
p.000026: 5.14.2 The sponsor should not supply an investigator/institution with the investigational product(s)
p.000026: until the sponsor obtains all required documentation (e.g., approval/favourable opinion from IRB/IEC and regulatory
p.000026: authority(ies)).
p.000026:
p.000026: 5.14.3 The sponsor should ensure that written procedures include instructions that the
p.000026: investigator/institution should follow for the handling and storage of investigational product(s) for the
p.000026: trial and documentation thereof. The procedures should address adequate and safe receipt, handling, storage,
p.000026: dispensing, retrieval of unused product from subjects, and return of unused investigational product(s) to the
p.000026: sponsor (or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory
p.000026: requirement(s)).
p.000026:
...
p.000049: appropriateness of instructions
p.000049: provided to the subjects
p.000049:
p.000049:
p.000049:
p.000049:
p.000049: 8.2.14
p.000049:
p.000049:
p.000049:
p.000049:
p.000049: 8.2.15
p.000049: INSTRUCTIONS FOR HANDLING OF INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALS
p.000049: (if not included in protocol or Investigator’s Brochure)
p.000049:
p.000049: SHIPPING RECORDS FOR INVESTIGATIONAL PRODUCT(S) AND TRIAL-RELATED MATERIALS
p.000049: To document instructions needed to ensure proper X X storage, packaging,
p.000049: dispensing and disposition of
p.000049: investigational products and trial-related materials
p.000049:
p.000049:
p.000049: To document shipment dates, batch numbers and X X method of shipment of
p.000049: investigational product(s)
p.000049: and trial-related materials. Allows tracking of product batch, review of shipping conditions, and
p.000049: accountability
p.000049:
p.000049:
p.000049:
p.000049:
p.000049:
p.000049:
p.000050: 50
p.000050:
p.000050: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000050:
p.000050:
p.000050: Title of Document
p.000050: Purpose
p.000050: Located in Files of
p.000050:
p.000050:
p.000050:
p.000050: 8.2.16
p.000050:
p.000050:
p.000050: CERTIFICATE(S) OF ANALYSIS OF INVESTIGATIONAL PRODUCT(S) SHIPPED
p.000050:
p.000050:
p.000050: To document identity, purity, and strength of investigational product(s) to be used in the trial
p.000050: Investigator/ Institution
p.000050: Sponsor
p.000050:
p.000050: X
p.000050:
p.000050:
p.000050:
p.000050: 8.2.17
p.000050: DECODING PROCEDURES FOR BLINDED TRIALS
p.000050: To document how, in case of an emergency, X identity of blinded investigational product
p.000050: can be
p.000050: revealed without breaking the blind for the remaining subjects' treatment
p.000050: X
p.000050: (third party if applicable)
p.000050:
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p.000050:
p.000051: 51
p.000051:
p.000051: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000051:
p.000051:
p.000051:
p.000051:
p.000051: Title of Document
p.000051: Purpose
p.000051: Located in Files of
p.000051:
p.000051:
p.000051:
p.000051: 8.2.18
p.000051:
p.000051:
p.000051: MASTER RANDOMISATION LIST
p.000051:
p.000051:
p.000051: To document method for randomisation of trial population
p.000051: Investigator/ Institution
p.000051: Sponsor
p.000051:
p.000051: X
p.000051: (third party if applicable)
p.000051:
p.000051:
p.000051:
p.000051: 8.2.19
p.000051:
p.000051: 8.2.20
p.000051: PRE-TRIAL MONITORING REPORT
p.000051:
p.000051: TRIAL INITIATION MONITORING REPORT
p.000051: To document that the site is suitable for the trial X (may be
p.000051: combined with 8.2.20)
p.000051:
p.000051: To document that trial procedures were reviewed X X with the investigator
p.000051: and the investigator’s trial
p.000051: staff ( may be combined with 8.2.19)
p.000051:
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General/Other / Relationship to Authority
Searching for indicator authority:
(return to top)
p.000011: 11
p.000011: 3.3 Procedures
p.000011: 11
p.000011: 3.4 Records
p.000012: 12
p.000012: 4. INVESTIGATOR
p.000013: 13
p.000013: 4.1 Investigator's Qualifications and Agreements
p.000013: 13
p.000013: 4.2 Adequate Resources
p.000013: 13
p.000013: 4.3 Medical Care of Trial Subjects
p.000014: 14
p.000014: 4.4 Communication with IRB/IEC
p.000014: 14
p.000014: 4.5 Compliance with Protocol
p.000014: 14
p.000014: 4.6 Investigational Product(s)
p.000015: 15
p.000015: 4.7 Randomization Procedures and Unblinding
p.000015: 15
p.000015: 4.8 Informed Consent of Trial Subjects
p.000016: 16
p.000016: 4.9 Records and Reports
p.000019: 19
p.000019: 4.10 Progress Reports
p.000019: 19
p.000019: 4.11 Safety Reporting
p.000020: 20
p.000020: 4.12 Premature Termination or Suspension of a Trial
p.000020: 20
p.000020: 4.13 Final Report(s) by Investigator
p.000020: 20
p.000020: 5. SPONSOR
p.000021: 21
p.000021: 5.0 Quality Management
p.000021: 21
p.000021: 5.1 Quality Assurance and Quality Control
p.000022: 22
p.000022: 5.2 Contract Research Organization (CRO)
p.000022: 22
p.000022: 5.3 Medical Expertise
p.000023: 23
p.000023: i
p.000023:
p.000023: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000023: 5.4 Trial Design
p.000023: 23
p.000023: 5.5 Trial Management, Data Handling, and Record Keeping 23
p.000023: 5.6 Investigator Selection
p.000025: 25
p.000025: 5.7 Allocation of Responsibilities
p.000025: 25
p.000025: 5.8 Compensation to Subjects and Investigators
p.000025: 25
p.000025: 5.9 Financing
p.000026: 26
p.000026: 5.10 Notification/Submission to Regulatory Authority(ies)
p.000026: 26
p.000026: 5.11 Confirmation of Review by IRB/IEC
p.000026: 26
p.000026: 5.12 Information on Investigational Product(s)
p.000026: 26
p.000026: 5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s) 27
p.000026: 5.14 Supplying and Handling Investigational Product(s)
p.000027: 27
p.000027: 5.15 Record Access
p.000028: 28
p.000028: 5.16 Safety Information
p.000028: 28
p.000028: 5.17 Adverse Drug Reaction Reporting
p.000028: 28
p.000028: 5.18 Monitoring
p.000029: 29
p.000029: 5.18.1 Purpose
p.000029: 29
p.000029: 5.18.2 Selection and Qualifications of Monitors 29
p.000029: 5.18.3 Extent and Nature of Monitoring
p.000029: 29
p.000029: 5.18.5 Monitoring Procedures
p.000031: 31
p.000031: 5.18.6 Monitoring Report
p.000032: 32
p.000032: 5.18.7 Monitoring Plan
p.000032: 32
p.000032: 5.19 Audit
p.000032: 32
p.000032: 5.19.1 Purpose
p.000032: 32
p.000032: 5.19.2 Selection and Qualification of Auditors 32
p.000032: 5.19.3 Auditing Procedures
p.000033: 33
p.000033: 5.20 Noncompliance
p.000033: 33
p.000033: 5.21 Premature Termination or Suspension of a Trial
p.000033: 33
p.000033: 5.22 Clinical Trial/Study Reports
p.000033: 33
p.000033: 5.23 Multicentre Trials
p.000034: 34
p.000034: 6. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S) 34
p.000034: 6.1 General Information
p.000034: 34
p.000034: 6.2 Background Information
p.000035: 35
p.000035: 6.3 Trial Objectives and Purpose
p.000035: 35
p.000035: 6.4 Trial Design
p.000035: 35
...
p.000003: of that protection, by, among other things, reviewing and approving/providing favourable opinion on, the trial
p.000003: protocol, the suitability of the investigator(s), facilities, and the methods and material to be used in obtaining and
p.000003: documenting informed consent of the trial subjects.
p.000003: The legal status, composition, function, operations and regulatory requirements pertaining to Independent
p.000003: Ethics Committees may differ among countries, but should allow the Independent Ethics Committee to act in agreement
p.000003: with GCP as described in this guideline.
p.000003:
p.000003:
p.000003:
p.000003:
p.000003:
p.000004: 4
p.000004:
p.000004: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000004:
p.000004: 1.28 Informed Consent
p.000004: A process by which a subject voluntarily confirms his or her willingness to participate in a particular
p.000004: trial, after having been informed of all aspects of the trial that are relevant to the subject's
p.000004: decision to participate. Informed consent is documented by means of a written, signed and dated informed consent form.
p.000004: 1.29 Inspection
p.000004: The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any
p.000004: other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located
p.000004: at the site of the trial, at the sponsor's and/or contract research organization’s (CRO’s) facilities,
p.000004: or at other establishments deemed appropriate by the regulatory authority(ies).
p.000004: 1.30 Institution (medical)
p.000004: Any public or private entity or agency or medical or dental facility where clinical trials are
p.000004: conducted.
p.000004: 1.31 Institutional Review Board (IRB)
p.000004: An independent body constituted of medical, scientific, and non-scientific members, whose responsibility is
p.000004: to ensure the protection of the rights, safety and well-being of human subjects involved in a trial by, among
p.000004: other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the
p.000004: methods and material to be used in obtaining and documenting informed consent of the trial subjects.
p.000004: 1.32 Interim Clinical Trial/Study Report
p.000004: A report of intermediate results and their evaluation based on analyses performed during the course of a
p.000004: trial.
p.000004: 1.33 Investigational Product
p.000004: A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial,
p.000004: including a product with a marketing authorization when used or assembled (formulated or packaged) in a
p.000004: way different from the approved form, or when used for an unapproved indication, or when used to gain further
p.000004: information about an approved use.
p.000004: 1.34 Investigator
p.000004: A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of
p.000004: individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal
p.000004: investigator. See also Subinvestigator.
p.000004: 1.35 Investigator/Institution
...
p.000010:
p.000010: Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial should vote/provide
p.000010: opinion on a trial-related matter.
p.000010:
p.000010: A list of IRB/IEC members and their qualifications should be maintained.
p.000010:
p.000010: 3.2.2 The IRB/IEC should perform its functions according to written operating procedures, should maintain
p.000010: written records of its activities and minutes of its meetings, and should comply with GCP and with the applicable
p.000010: regulatory requirement(s).
p.000010:
p.000010: 3.2.3 An IRB/IEC should make its decisions at announced meetings at which at least a quorum, as
p.000010: stipulated in its written operating procedures, is present.
p.000010:
p.000010: 3.2.4 Only members who participate in the IRB/IEC review and discussion should vote/provide
p.000010: their opinion and/or advise.
p.000010:
p.000010: 3.2.5 The investigator may provide information on any aspect of the trial, but should not participate
p.000010: in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC.
p.000010:
p.000010: 3.2.6 An IRB/IEC may invite nonmembers with expertise in special areas for assistance.
p.000010:
p.000010: 3.3 Procedures
p.000010: The IRB/IEC should establish, document in writing, and follow its procedures, which should include:
p.000010:
p.000010:
p.000011: 11
p.000011:
p.000011: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000011:
p.000011: 3.3.1 Determining its composition (names and qualifications of the members) and the authority under which it is
p.000011: established.
p.000011:
p.000011: 3.3.2 Scheduling, notifying its members of, and conducting its meetings.
p.000011:
p.000011: 3.3.3 Conducting initial and continuing review of trials.
p.000011:
p.000011: 3.3.4 Determining the frequency of continuing review, as appropriate.
p.000011:
p.000011: 3.3.5 Providing, according to the applicable regulatory requirements, expedited review and
p.000011: approval/favourable opinion of minor change(s) in ongoing trials that have the approval/favourable
p.000011: opinion of the IRB/IEC.
p.000011:
p.000011: 3.3.6 Specifying that no subject should be admitted to a trial before the IRB/IEC issues its written
p.000011: approval/favourable opinion of the trial.
p.000011:
p.000011: 3.3.7 Specifying that no deviations from, or changes of, the protocol should be initiated without
p.000011: prior written IRB/IEC approval/favourable opinion of an appropriate amendment, except when
p.000011: necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or
p.000011: administrative aspects of the trial (e.g., change of monitor(s), telephone number(s)) (see 4.5.2).
p.000011:
p.000011: 3.3.8 Specifying that the investigator should promptly report to the IRB/IEC:
p.000011: (a) Deviations from, or changes of, the protocol to eliminate immediate hazards to the trial subjects (see 3.3.7,
p.000011: 4.5.2, 4.5.4).
p.000011: (b) Changes increasing the risk to subjects and/or affecting significantly the conduct of the trial (see 4.10.2).
p.000011: (c) All adverse drug reactions (ADRs) that are both serious and unexpected.
p.000011: (d) New information that may affect adversely the safety of the subjects or the conduct of the trial.
p.000011:
p.000011: 3.3.9 Ensuring that the IRB/IEC promptly notify in writing the investigator/institution
p.000011: concerning:
p.000011: (a) Its trial-related decisions/opinions.
p.000011: (b) The reasons for its decisions/opinions.
p.000011: (c) Procedures for appeal of its decisions/opinions.
p.000011:
p.000011: 3.4 Records
p.000011: The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists, lists of
p.000011: occupations/affiliations of members, submitted documents, minutes of meetings, and correspondence) for
p.000011: a period of at least 3-years after completion of the trial and make them available upon request from the
p.000011: regulatory authority(ies).
p.000011: The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide its written
p.000011: procedures and membership lists.
p.000011:
p.000011:
p.000011:
p.000011:
p.000011:
p.000011:
p.000012: 12
p.000012:
p.000012: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000012:
p.000012: 4. INVESTIGATOR
p.000012:
p.000012: 4.1 Investigator's Qualifications and Agreements
p.000012:
p.000012: 4.1.1 The investigator(s) should be qualified by education, training, and experience to assume responsibility for
p.000012: the proper conduct of the trial, should meet all the qualifications specified by the applicable
p.000012: regulatory requirement(s), and should provide evidence of such qualifications through up-to-date
p.000012: curriculum vitae and/or other relevant documentation requested by the sponsor, the IRB/IEC,
p.000012: and/or the regulatory authority(ies).
p.000012:
p.000012: 4.1.2 The investigator should be thoroughly familiar with the appropriate use of the
p.000012: investigational product(s), as described in the protocol, in the current Investigator's Brochure, in the
p.000012: product information and in other information sources provided by the sponsor.
p.000012:
p.000012: 4.1.3 The investigator should be aware of, and should comply with, GCP and the applicable regulatory requirements.
p.000012:
p.000012: 4.1.4 The investigator/institution should permit monitoring and auditing by the sponsor, and inspection by
p.000012: the appropriate regulatory authority(ies).
p.000012:
p.000012: 4.1.5 The investigator should maintain a list of appropriately qualified persons to whom the investigator
p.000012: has delegated significant trial-related duties.
p.000012:
p.000012: 4.2 Adequate Resources
p.000012:
p.000012: 4.2.1 The investigator should be able to demonstrate (e.g., based on retrospective data) a potential
p.000012: for recruiting the required number of suitable subjects within the agreed recruitment period.
p.000012:
p.000012: 4.2.2 The investigator should have sufficient time to properly conduct and complete the trial within the agreed
p.000012: trial period.
p.000012:
p.000012: 4.2.3 The investigator should have available an adequate number of qualified staff and adequate
p.000012: facilities for the foreseen duration of the trial to conduct the trial properly and safely.
p.000012:
p.000012: 4.2.4 The investigator should ensure that all persons assisting with the trial are adequately informed
p.000012: about the protocol, the investigational product(s), and their trial-related duties and functions.
p.000012:
p.000012: ADDENDUM
p.000012: 4.2.5 The investigator is responsible for supervising any individual or party to whom the investigator
p.000012: delegates trial-related duties and functions conducted at the trial site.
p.000012:
p.000012: 4.2.6 If the investigator/institution retains the services of any individual or party to perform
p.000012: trial-related duties and functions, the investigator/institution should ensure this individual or party is qualified
p.000012: to perform those trial-related duties and functions and should implement procedures to ensure the
...
p.000013: being informed.
p.000013:
p.000013: 4.3.4 Although a subject is not obliged to give his/her reason(s) for withdrawing prematurely from a trial, the
p.000013: investigator should make a reasonable effort to ascertain the reason(s), while fully respecting the subject's rights.
p.000013:
p.000013: 4.4 Communication with IRB/IEC
p.000013:
p.000013: 4.4.1 Before initiating a trial, the investigator/institution should have written and dated
p.000013: approval/favourable opinion from the IRB/IEC for the trial protocol, written informed consent form,
p.000013: consent form updates, subject recruitment procedures (e.g., advertisements), and any other written
p.000013: information to be provided to subjects.
p.000013:
p.000013: 4.4.2 As part of the investigator's/institution’s written application to the IRB/IEC, the
p.000013: investigator/institution should provide the IRB/IEC with a current copy of the Investigator's
p.000013: Brochure. If the Investigator's Brochure is updated during the trial, the investigator/institution should
p.000013: supply a copy of the updated Investigator’s Brochure to the IRB/IEC.
p.000013:
p.000013: 4.4.3 During the trial the investigator/institution should provide to the IRB/IEC all documents subject to review.
p.000013:
p.000013: 4.5 Compliance with Protocol
p.000013:
p.000013: 4.5.1 The investigator/institution should conduct the trial in compliance with the protocol agreed to by
p.000013: the sponsor and, if required, by the regulatory authority(ies) and which was given approval/favourable opinion by the
p.000013: IRB/IEC. The investigator/institution and the sponsor should sign the protocol, or an alternative contract, to confirm
p.000013: agreement.
p.000013:
p.000013: 4.5.2 The investigator should not implement any deviation from, or changes of the protocol without
p.000013: agreement by the sponsor and prior review and documented approval/favourable opinion from the IRB/IEC of an
p.000013: amendment, except where necessary to eliminate an immediate hazard(s) to trial subjects, or when the change(s)
p.000013: involves only logistical or administrative aspects of the trial (e.g., change in monitor(s), change of
p.000013: telephone number(s)).
p.000013:
p.000013:
p.000013:
p.000013:
p.000014: 14
p.000014:
p.000014: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000014:
p.000014: 4.5.3 The investigator, or person designated by the investigator, should document and explain any deviation from the
p.000014: approved protocol.
p.000014:
p.000014: 4.5.4 The investigator may implement a deviation from, or a change of, the protocol to eliminate an
p.000014: immediate hazard(s) to trial subjects without prior IRB/IEC approval/favourable opinion. As soon
p.000014: as possible, the implemented deviation or change, the reasons for it, and, if appropriate, the proposed
p.000014: protocol amendment(s) should be submitted:
p.000014: (a) to the IRB/IEC for review and approval/favourable opinion,
p.000014: (b) to the sponsor for agreement and, if required,
p.000014: (c) to the regulatory authority(ies).
p.000014:
p.000014: 4.6 Investigational Product(s)
p.000014:
p.000014: 4.6.1 Responsibility for investigational product(s) accountability at the trial site(s) rests with the
p.000014: investigator/institution.
p.000014:
p.000014: 4.6.2 Where allowed/required, the investigator/institution may/should assign some or all of the
p.000014: investigator's/institution’s duties for investigational product(s) accountability at the trial site(s) to an
p.000014: appropriate pharmacist or another appropriate individual who is under the supervision of the
p.000014: investigator/institution..
p.000014:
p.000014: 4.6.3 The investigator/institution and/or a pharmacist or other appropriate individual, who is designated
p.000014: by the investigator/institution, should maintain records of the product's delivery to the trial site, the
p.000014: inventory at the site, the use by each subject, and the return to the sponsor or alternative disposition of
p.000014: unused product(s). These records should include dates, quantities, batch/serial numbers, expiration dates
p.000014: (if applicable), and the unique code numbers assigned to the investigational product(s) and trial
p.000014: subjects. Investigators should maintain records that document adequately that the subjects were provided the
p.000014: doses specified by the protocol and reconcile all investigational product(s) received from the sponsor.
p.000014:
p.000014: 4.6.4 The investigational product(s) should be stored as specified by the sponsor (see 5.13.2 and 5.14.3) and in
p.000014: accordance with applicable regulatory requirement(s).
p.000014:
p.000014: 4.6.5 The investigator should ensure that the investigational product(s) are used only in accordance with
p.000014: the approved protocol.
p.000014:
...
p.000016: information to be provided to subjects should include explanations of the following:
p.000016: (a) That the trial involves research.
p.000016: (b) The purpose of the trial.
p.000016: (c) The trial treatment(s) and the probability for random assignment to each treatment.
p.000016: (d) The trial procedures to be followed, including all invasive procedures.
p.000016: (e) The subject's responsibilities.
p.000016: (f) Those aspects of the trial that are experimental.
p.000016: (g) The reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo,
p.000016: fetus, or nursing infant.
p.000016: (h) The reasonably expected benefits. When there is no intended clinical benefit to the subject, the subject should be
p.000016: made aware of this.
p.000016: (i) The alternative procedure(s) or course(s) of treatment that may be available to the subject, and their
p.000016: important potential benefits and risks.
p.000016: (j) The compensation and/or treatment available to the subject in the event of trial- related injury.
p.000016: (k) The anticipated prorated payment, if any, to the subject for participating in the trial.
p.000016: (l) The anticipated expenses, if any, to the subject for participating in the trial.
p.000016: (m) That the subject's participation in the trial is voluntary and that the subject may refuse to
p.000016: participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is
p.000016: otherwise entitled.
p.000016: (n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory authority(ies) will be granted
p.000016: direct access to the subject's original medical records for verification of clinical trial procedures and/or data,
p.000016: without violating the confidentiality of the subject, to the extent permitted by the applicable laws and
p.000016: regulations and that, by signing a written informed consent form, the subject or the subject's legally
p.000016: acceptable representative is authorizing such access.
p.000016: (o) That records identifying the subject will be kept confidential and, to the extent permitted by the
p.000016: applicable laws and/or regulations, will not be made publicly available. If the results of the trial are
p.000016: published, the subject’s identity will remain confidential.
p.000016: (p) That the subject or the subject's legally acceptable representative will be informed in a timely manner if
p.000016: information becomes available that may be relevant to the subject's willingness to continue participation in
p.000016: the trial.
p.000016:
p.000017: 17
p.000017:
p.000017: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000017:
p.000017: (q) The person(s) to contact for further information regarding the trial and the rights of trial subjects, and whom to
p.000017: contact in the event of trial-related injury.
p.000017: (r) The foreseeable circumstances and/or reasons under which the subject's participation in the trial may be
p.000017: terminated.
p.000017: (s) The expected duration of the subject's participation in the trial.
p.000017: (t) The approximate number of subjects involved in the trial.
p.000017:
...
p.000018: investigators and/or the investigators' designated representatives on making such corrections. Sponsors
p.000018: should have written procedures to assure that changes or corrections in CRFs made by sponsor's designated
p.000018: representatives are documented, are necessary, and are endorsed by the investigator. The investigator should retain
p.000018: records of the changes and corrections.
p.000018:
p.000018: 4.9.4 The investigator/institution should maintain the trial documents as specified in Essential Documents for the
p.000018: Conduct of a Clinical Trial (see 8.) and as required by the applicable regulatory requirement(s). The
p.000018: investigator/institution should take measures to prevent accidental or premature destruction of these documents.
p.000018:
p.000018: 4.9.5 Essential documents should be retained until at least 2-years after the last approval of a marketing
p.000018: application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or
p.000018: at least 2-years have elapsed since the formal discontinuation of clinical development of the investigational product.
p.000018: These documents should be retained for a longer period however if required by the applicable regulatory requirements or
p.000018: by an agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator/institution as to
p.000018: when these documents no longer need to be retained (see 5.5.12).
p.000018:
p.000018: 4.9.6 The financial aspects of the trial should be documented in an agreement between the sponsor and
p.000018: the investigator/institution.
p.000018:
p.000018: 4.9.7 Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the
p.000018: investigator/institution should make available for direct access all requested trial-related records.
p.000018:
p.000018: 4.10 Progress Reports
p.000018:
p.000018: 4.10.1 The investigator should submit written summaries of the trial status to the IRB/IEC annually, or
p.000018: more frequently, if requested by the IRB/IEC.
p.000018:
p.000019: 19
p.000019:
p.000019: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000019:
p.000019: 4.10.2 The investigator should promptly provide written reports to the sponsor, the IRB/IEC (see 3.3.8)
p.000019: and, where applicable, the institution on any changes significantly affecting the conduct of the trial, and/or
p.000019: increasing the risk to subjects.
p.000019:
p.000019: 4.11 Safety Reporting
p.000019:
p.000019: 4.11.1 All serious adverse events (SAEs) should be reported immediately to the sponsor except for those SAEs that
p.000019: the protocol or other document (e.g., Investigator's Brochure) identifies as not needing immediate reporting.
p.000019: The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up
p.000019: reports should identify subjects by unique code numbers assigned to the trial subjects rather than by the subjects'
p.000019: names, personal identification numbers, and/or addresses. The investigator should also comply with the
p.000019: applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to
p.000019: the regulatory authority(ies) and the IRB/IEC.
p.000019:
p.000019: 4.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as critical to safety
p.000019: evaluations should be reported to the sponsor according to the reporting requirements and within
p.000019: the time periods specified by the sponsor in the protocol.
p.000019:
p.000019: 4.11.3 For reported deaths, the investigator should supply the sponsor and the IRB/IEC with any additional requested
p.000019: information (e.g., autopsy reports and terminal medical reports).
p.000019:
p.000019: 4.12 Premature Termination or Suspension of a Trial
p.000019: If the trial is prematurely terminated or suspended for any reason, the investigator/institution should
p.000019: promptly inform the trial subjects, should assure appropriate therapy and follow-up for the subjects, and, where
p.000019: required by the applicable regulatory requirement(s), should inform the regulatory authority(ies). In addition:
p.000019:
p.000019: 4.12.1 If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator
p.000019: should inform the institution where applicable, and the investigator/institution should promptly
p.000019: inform the sponsor and the IRB/IEC, and should provide the sponsor and the IRB/IEC a detailed written explanation of
p.000019: the termination or suspension.
p.000019:
p.000019: 4.12.2 If the sponsor terminates or suspends a trial (see 5.21), the investigator should promptly inform the
p.000019: institution where applicable and the investigator/institution should promptly inform the IRB/IEC and provide the
p.000019: IRB/IEC a detailed written explanation of the termination or suspension.
p.000019:
p.000019: 4.12.3 If the IRB/IEC terminates or suspends its approval/favourable opinion of a trial (see 3.1.2 and 3.3.9), the
p.000019: investigator should inform the institution where applicable and the investigator/institution should promptly
p.000019: notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension.
p.000019:
p.000019: 4.13 Final Report(s) by Investigator
p.000019: Upon completion of the trial, the investigator, where applicable, should inform the institution; the
p.000019: investigator/institution should provide the IRB/IEC with a summary of the trial’s outcome, and the regulatory
p.000019: authority(ies) with any reports required.
p.000019:
p.000019:
p.000019:
p.000020: 20
p.000020:
p.000020: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000020:
p.000020: 5. SPONSOR ADDENDUM
p.000020: 5.0 Quality Management
p.000020: The sponsor should implement a system to manage quality throughout all stages of the trial process.
p.000020: Sponsors should focus on trial activities essential to ensuring human subject protection and the reliability of trial
p.000020: results. Quality management includes the design of efficient clinical trial protocols and tools and
p.000020: procedures for data collection and processing, as well as the collection of information that is essential to decision
p.000020: making.
p.000020: The methods used to assure and control the quality of the trial should be proportionate to the risks inherent in
p.000020: the trial and the importance of the information collected. The sponsor should ensure that all aspects of the
p.000020: trial are operationally feasible and should avoid unnecessary complexity, procedures, and data collection.
p.000020: Protocols, case report forms, and other operational documents should be clear, concise, and consistent.
p.000020: The quality management system should use a risk-based approach as described below.
p.000020:
p.000020: 5.0.1 Critical Process and Data Identification
p.000020: During protocol development, the sponsor should identify those processes and data that are critical to ensure human
p.000020: subject protection and the reliability of trial results.
p.000020:
p.000020: 5.0.2 Risk Identification
...
p.000023: is particularly important when making changes to the computerized systems, such as software upgrades or
p.000023: migration of data.
p.000023: 5.5.4 If data are transformed during processing, it should always be possible to compare the original data and
p.000023: observations with the processed data.
p.000023:
p.000023: 5.5.5 The sponsor should use an unambiguous subject identification code (see 1.58) that allows identification of all
p.000023: the data reported for each subject.
p.000023:
p.000023: 5.5.6 The sponsor, or other owners of the data, should retain all of the sponsor-specific essential
p.000023: documents pertaining to the trial (see 8. Essential Documents for the Conduct of a Clinical Trial).
p.000023:
p.000023: 5.5.7 The sponsor should retain all sponsor-specific essential documents in conformance with the applicable
p.000023: regulatory requirement(s) of the country(ies) where the product is approved, and/or where the sponsor
p.000023: intends to apply for approval(s).
p.000023:
p.000023: 5.5.8 If the sponsor discontinues the clinical development of an investigational product (i.e., for any or all
p.000023: indications, routes of administration, or dosage forms), the sponsor should maintain all sponsor-specific essential
p.000023: documents for at least 2-years after formal discontinuation or in conformance with the applicable regulatory
p.000023: requirement(s).
p.000023:
p.000023: 5.5.9 If the sponsor discontinues the clinical development of an investigational product, the sponsor
p.000023: should notify all the trial investigators/institutions and all the regulatory authorities.
p.000023:
p.000023: 5.5.10 Any transfer of ownership of the data should be reported to the appropriate authority(ies), as required by the
p.000023: applicable regulatory requirement(s).
p.000023:
p.000023:
p.000024: 24
p.000024:
p.000024: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000024:
p.000024: 5.5.11 The sponsor specific essential documents should be retained until at least 2-years after the last approval
p.000024: of a marketing application in an ICH region and until there are no pending or contemplated marketing
p.000024: applications in an ICH region or at least 2-years have elapsed since the formal discontinuation of clinical
p.000024: development of the investigational product. These documents should be retained for a longer period however if
p.000024: required by the applicable regulatory requirement(s) or if needed by the sponsor.
p.000024:
p.000024: 5.5.12 The sponsor should inform the investigator(s)/institution(s) in writing of the need for record
p.000024: retention and should notify the investigator(s)/institution(s) in writing when the trial related records are no
p.000024: longer needed.
p.000024:
p.000024: 5.6 Investigator Selection
p.000024:
p.000024: 5.6.1 The sponsor is responsible for selecting the investigator(s)/institution(s). Each investigator
p.000024: should be qualified by training and experience and should have adequate resources (see 4.1, 4.2) to properly
p.000024: conduct the trial for which the investigator is selected. If organization of a coordinating committee
p.000024: and/or selection of coordinating investigator(s) are to be utilized in multicentre trials, their organization
p.000024: and/or selection are the sponsor's responsibility.
p.000024:
p.000024: 5.6.2 Before entering an agreement with an investigator/institution to conduct a trial, the sponsor
...
p.000024: (d) to retain the trial related essential documents until the sponsor informs the
p.000024: investigator/institution these documents are no longer needed (see 4.9.4 and 5.5.12).
p.000024: The sponsor and the investigator/institution should sign the protocol, or an alternative document, to
p.000024: confirm this agreement.
p.000024:
p.000024: 5.7 Allocation of Responsibilities
p.000024: Prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related duties and functions.
p.000024:
p.000024: 5.8 Compensation to Subjects and Investigators
p.000024:
p.000024: 5.8.1 If required by the applicable regulatory requirement(s), the sponsor should provide insurance or
p.000024: should indemnify (legal and financial coverage) the investigator/the institution against claims
p.000024: arising from the trial, except for claims that arise from malpractice and/or negligence.
p.000024:
p.000024:
p.000024:
p.000024:
p.000025: 25
p.000025:
p.000025: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000025:
p.000025: 5.8.2 The sponsor's policies and procedures should address the costs of treatment of trial subjects in
p.000025: the event of trial-related injuries in accordance with the applicable regulatory requirement(s).
p.000025:
p.000025: 5.8.3 When trial subjects receive compensation, the method and manner of compensation should comply with
p.000025: applicable regulatory requirement(s).
p.000025:
p.000025: 5.9 Financing
p.000025: The financial aspects of the trial should be documented in an agreement between the sponsor and the
p.000025: investigator/institution.
p.000025:
p.000025: 5.10 Notification/Submission to Regulatory Authority(ies)
p.000025: Before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator, if required by the
p.000025: applicable regulatory requirement(s)) should submit any required application(s) to the appropriate
p.000025: authority(ies) for review, acceptance, and/or permission (as required by the applicable regulatory
p.000025: requirement(s)) to begin the trial(s). Any notification/submission should be dated and contain sufficient information
p.000025: to identify the protocol.
p.000025:
p.000025: 5.11 Confirmation of Review by IRB/IEC
p.000025:
p.000025: 5.11.1 The sponsor should obtain from the investigator/institution:
p.000025: (a) The name and address of the investigator's/institution’s IRB/IEC.
p.000025: (b) A statement obtained from the IRB/IEC that it is organized and operates according to GCP and the applicable laws
p.000025: and regulations.
p.000025: (c) Documented IRB/IEC approval/favourable opinion and, if requested by the sponsor, a current copy of protocol,
p.000025: written informed consent form(s) and any other written information to be provided to subjects, subject recruiting
p.000025: procedures, and documents related to payments and compensation available to the subjects, and any other
p.000025: documents that the IRB/IEC may have requested.
p.000025:
p.000025: 5.11.2 If the IRB/IEC conditions its approval/favourable opinion upon change(s) in any aspect of the trial, such as
p.000025: modification(s) of the protocol, written informed consent form and any other written information to be provided
p.000025: to subjects, and/or other procedures, the sponsor should obtain from the investigator/institution a copy
p.000025: of the modification(s) made and the date approval/favourable opinion was given by the IRB/IEC.
p.000025:
...
p.000026: (e.g., monitors, investigators, pharmacists, storage managers) of these determinations.
p.000026:
p.000026: 5.13.3 The investigational product(s) should be packaged to prevent contamination and unacceptable
p.000026: deterioration during transport and storage.
p.000026:
p.000026: 5.13.4 In blinded trials, the coding system for the investigational product(s) should include a mechanism
p.000026: that permits rapid identification of the product(s) in case of a medical emergency, but does not permit
p.000026: undetectable breaks of the blinding.
p.000026:
p.000026: 5.13.5 If significant formulation changes are made in the investigational or comparator product(s)
p.000026: during the course of clinical development, the results of any additional studies of the formulated product(s)
p.000026: (e.g., stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly
p.000026: alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in
p.000026: clinical trials.
p.000026:
p.000026: 5.14 Supplying and Handling Investigational Product(s)
p.000026:
p.000026: 5.14.1 The sponsor is responsible for supplying the investigator(s)/institution(s) with the investigational
p.000026: product(s).
p.000026:
p.000026: 5.14.2 The sponsor should not supply an investigator/institution with the investigational product(s)
p.000026: until the sponsor obtains all required documentation (e.g., approval/favourable opinion from IRB/IEC and regulatory
p.000026: authority(ies)).
p.000026:
p.000026: 5.14.3 The sponsor should ensure that written procedures include instructions that the
p.000026: investigator/institution should follow for the handling and storage of investigational product(s) for the
p.000026: trial and documentation thereof. The procedures should address adequate and safe receipt, handling, storage,
p.000026: dispensing, retrieval of unused product from subjects, and return of unused investigational product(s) to the
p.000026: sponsor (or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory
p.000026: requirement(s)).
p.000026:
p.000026: 5.14.4 The sponsor should:
p.000026: (a) Ensure timely delivery of investigational product(s) to the investigator(s).
p.000026: (b) Maintain records that document shipment, receipt, disposition, return, and destruction of the
p.000026: investigational product(s) (see 8. Essential Documents for the Conduct of a Clinical Trial).
p.000026:
p.000026:
p.000026:
p.000027: 27
p.000027:
p.000027: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000027:
p.000027: (c) Maintain a system for retrieving investigational products and documenting this retrieval (e.g., for
p.000027: deficient product recall, reclaim after trial completion, expired product reclaim).
p.000027: (d) Maintain a system for the disposition of unused investigational product(s) and for the documentation of this
p.000027: disposition.
p.000027:
p.000027: 5.14.5 The sponsor should:
p.000027: (a) Take steps to ensure that the investigational product(s) are stable over the period of use.
p.000027: (b) Maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm
p.000027: specifications, should this become necessary, and maintain records of batch sample analyses and
p.000027: characteristics. To the extent stability permits, samples should be retained either until the analyses of
p.000027: the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the
p.000027: longer retention period.
p.000027:
p.000027: 5.15 Record Access
p.000027:
p.000027: 5.15.1 The sponsor should ensure that it is specified in the protocol or other written agreement that the
p.000027: investigator(s)/institution(s) provide direct access to source data/documents for trial-related monitoring, audits,
p.000027: IRB/IEC review, and regulatory inspection.
p.000027:
p.000027: 5.15.2 The sponsor should verify that each subject has consented, in writing, to direct access to his/her original
p.000027: medical records for trial-related monitoring, audit, IRB/IEC review, and regulatory inspection.
p.000027:
p.000027: 5.16 Safety Information
p.000027:
p.000027: 5.16.1 The sponsor is responsible for the ongoing safety evaluation of the investigational product(s).
p.000027:
p.000027: 5.16.2 The sponsor should promptly notify all concerned investigator(s)/institution(s) and the regulatory
p.000027: authority(ies) of findings that could affect adversely the safety of subjects, impact the conduct of the
p.000027: trial, or alter the IRB/IEC's approval/favourable opinion to continue the trial.
p.000027:
p.000027: 5.17 Adverse Drug Reaction Reporting
p.000027:
p.000027: 5.17.1 The sponsor should expedite the reporting to all concerned investigator(s)/institutions(s), to the
p.000027: IRB(s)/IEC(s), where required, and to the regulatory authority(ies) of all adverse drug reactions (ADRs) that are both
p.000027: serious and unexpected.
p.000027:
p.000027: 5.17.2 Such expedited reports should comply with the applicable regulatory requirement(s) and with the ICH Guideline
p.000027: for Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.
p.000027:
p.000027: 5.17.3 The sponsor should submit to the regulatory authority(ies) all safety updates and periodic reports, as required
p.000027: by applicable regulatory requirement(s).
p.000027:
p.000027:
p.000027:
p.000028: 28
p.000028:
p.000028: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000028:
p.000028:
p.000028: 5.18 Monitoring
p.000028:
p.000028: 5.18.1 Purpose
p.000028: The purposes of trial monitoring are to verify that:
p.000028: (a) The rights and well-being of human subjects are protected.
p.000028: (b) The reported trial data are accurate, complete, and verifiable from source documents.
p.000028: (c) The conduct of the trial is in compliance with the currently approved
p.000028: protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).
p.000028:
p.000028: 5.18.2 Selection and Qualifications of Monitors
p.000028: (a) Monitors should be appointed by the sponsor.
p.000028: (b) Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge
p.000028: needed to monitor the trial adequately. A monitor’s qualifications should be documented.
p.000028: (c) Monitors should be thoroughly familiar with the investigational product(s), the protocol, written
p.000028: informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs,
p.000028: GCP, and the applicable regulatory requirement(s).
p.000028:
p.000028: 5.18.3 Extent and Nature of Monitoring
p.000028: The sponsor should ensure that the trials are adequately monitored. The sponsor should determine the appropriate
p.000028: extent and nature of monitoring. The determination of the extent and nature of monitoring should be based on
...
p.000031:
p.000031: 5.19.1 Purpose
p.000031: The purpose of a sponsor's audit, which is independent of and separate from routine monitoring or
p.000031: quality control functions, should be to evaluate trial conduct and compliance with the protocol,
p.000031: SOPs, GCP, and the applicable regulatory requirements.
p.000031:
p.000031: 5.19.2 Selection and Qualification of Auditors
p.000031: (a) The sponsor should appoint individuals, who are independent of the clinical trials/systems,
p.000031: to conduct audits.
p.000031: (b) The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly.
p.000031: An auditor’s qualifications should be documented.
p.000031:
p.000031:
p.000031:
p.000031:
p.000031:
p.000032: 32
p.000032:
p.000032: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000032:
p.000032:
p.000032: 5.19.3 Auditing Procedures
p.000032: (a) The sponsor should ensure that the auditing of clinical trials/systems is conducted in accordance with the
p.000032: sponsor's written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit
p.000032: reports.
p.000032: (b) The sponsor's audit plan and procedures for a trial audit should be guided by the importance of
p.000032: the trial to submissions to regulatory authorities, the number of subjects in the trial, the type and
p.000032: complexity of the trial, the level of risks to the trial subjects, and any identified problem(s).
p.000032: (c) The observations and findings of the auditor(s) should be documented.
p.000032: (d) To preserve the independence and value of the audit function, the regulatory authority(ies) should not
p.000032: routinely request the audit reports. Regulatory authority(ies) may seek access to an audit report on a case by case
p.000032: basis when evidence of serious GCP non-compliance exists, or in the course of legal proceedings.
p.000032: (e) When required by applicable law or regulation, the sponsor should provide an audit certificate.
p.000032:
p.000032: 5.20 Noncompliance
p.000032:
p.000032: 5.20.1 Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s)
p.000032: by an investigator/institution, or by member(s) of the sponsor's staff should lead to prompt action by the
p.000032: sponsor to secure compliance.
p.000032: ADDENDUM
p.000032: If noncompliance that significantly affects or has the potential to significantly affect human subject
p.000032: protection or reliability of trial results is discovered, the sponsor should perform a root cause analysis and
p.000032: implement appropriate corrective and preventive actions.
p.000032: 5.20.2 If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an
p.000032: investigator/institution, the sponsor should terminate the investiga- tor's/institution’s participation in the
p.000032: trial. When an investigator's/institution’s parti- cipation is terminated because of noncompliance, the sponsor
p.000032: should notify promptly the regulatory authority(ies).
p.000032:
p.000032: 5.21 Premature Termination or Suspension of a Trial
p.000032: If a trial is prematurely terminated or suspended, the sponsor should promptly inform the
p.000032: investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the reason(s) for
p.000032: the termination or suspension. The IRB/IEC should also be informed promptly and provided the reason(s) for the
p.000032: termination or suspension by the sponsor or by the investigator/institution, as specified by the applicable
p.000032: regulatory requirement(s).
p.000032:
p.000032: 5.22 Clinical Trial/Study Reports
p.000032: Whether the trial is completed or prematurely terminated, the sponsor should ensure that the clinical
p.000032: trial reports are prepared and provided to the regulatory agency(ies) as required by the applicable regulatory
p.000032: requirement(s). The sponsor should also ensure that the clinical trial reports in marketing applications meet the
p.000032: standards of the ICH Guideline for Structure and Content of
p.000032:
p.000032:
p.000032:
p.000033: 33
p.000033:
p.000033: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000033:
p.000033: Clinical Study Reports. (NOTE: The ICH Guideline for Structure and Content of Clinical Study Reports specifies that
p.000033: abbreviated study reports may be acceptable in certain cases.)
p.000033:
p.000033: 5.23 Multicentre Trials
p.000033: For multicentre trials, the sponsor should ensure that:
p.000033:
p.000033: 5.23.1 All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor and, if
p.000033: required, by the regulatory authority(ies), and given approval/favourable opinion by the IRB/IEC.
p.000033:
p.000033: 5.23.2 The CRFs are designed to capture the required data at all multicentre trial sites. For those investigators who
p.000033: are collecting additional data, supplemental CRFs should also be provided that are designed to capture the
p.000033: additional data.
p.000033:
p.000033: 5.23.3 The responsibilities of coordinating investigator(s) and the other participating investigators
p.000033: are documented prior to the start of the trial.
p.000033:
p.000033: 5.23.4 All investigators are given instructions on following the protocol, on complying with a uniform set of
p.000033: standards for the assessment of clinical and laboratory findings, and on completing the CRFs.
p.000033:
p.000033: 5.23.5 Communication between investigators is facilitated.
p.000033:
p.000033: 6. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S)
p.000033: The contents of a trial protocol should generally include the following topics. However, site specific
p.000033: information may be provided on separate protocol page(s), or addressed in a separate agreement, and some of the
p.000033: information listed below may be contained in other protocol referenced documents, such as an Investigator’s
p.000033: Brochure.
p.000033:
p.000033: 6.1 General Information
p.000033:
p.000033: 6.1.1 Protocol title, protocol identifying number, and date. Any amendment(s) should also bear the amendment
p.000033: number(s) and date(s).
p.000033:
p.000033: 6.1.2 Name and address of the sponsor and monitor (if other than the sponsor).
p.000033:
p.000033: 6.1.3 Name and title of the person(s) authorized to sign the protocol and the protocol amendment(s) for
p.000033: the sponsor.
p.000033:
...
p.000043: 6.3 Marketing Experience
p.000043: ......................................................................................................
p.000043: 7 Summary of Data and Guidance for the Investigator ......................................................
p.000043:
p.000043: NB: References on 1. Publications
p.000043: 2. Reports
p.000043: These references should be found at the end of each chapter Appendices (if any)
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000043:
p.000044: 44
p.000044:
p.000044: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000044:
p.000044:
p.000044: 8. ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL
p.000044:
p.000044: 8.1 Introduction
p.000044: Essential Documents are those documents which individually and collectively permit evaluation of the conduct of a trial
p.000044: and the quality of the data produced. These documents serve to demonstrate the compliance of the
p.000044: investigator, sponsor and monitor with the standards of Good Clinical Practice and with all applicable
p.000044: regulatory requirements.
p.000044: Essential Documents also serve a number of other important purposes. Filing essential documents at the
p.000044: investigator/institution and sponsor sites in a timely manner can greatly assist in the successful management of a
p.000044: trial by the investigator, sponsor and monitor. These documents are also the ones which are usually audited by
p.000044: the sponsor's independent audit function and inspected by the regulatory authority(ies) as part of the
p.000044: process to confirm the validity of the trial conduct and the integrity of data collected.
p.000044: The minimum list of essential documents which has been developed follows. The various documents are grouped in three
p.000044: sections according to the stage of the trial during which they will normally be generated: 1) before the clinical phase
p.000044: of the trial commences, 2) during the clinical conduct of the trial, and 3) after completion or termination of the
p.000044: trial. A description is given of the purpose of each document, and whether it should be filed in either the
p.000044: investigator/institution or sponsor files, or both. It is acceptable to combine some of the documents, provided the
p.000044: individual elements are readily identifiable.
p.000044: Trial master files should be established at the beginning of the trial, both at the investigator/institution’s site and
p.000044: at the sponsor's office. A final close-out of a trial can only be done when the monitor has reviewed both
p.000044: investigator/institution and sponsor files and confirmed that all necessary documents are in the appropriate
p.000044: files.
p.000044: Any or all of the documents addressed in this guideline may be subject to, and should be available
p.000044: for, audit by the sponsor’s auditor and inspection by the regulatory authority(ies).
p.000044: ADDENDUM
p.000044: The sponsor and investigator/institution should maintain a record of the location(s) of their respective
p.000044: essential documents including source documents. The storage system used during the trial and for archiving
p.000044: (irrespective of the type of media used) should provide for document identification, version history, search,
p.000044: and retrieval.
p.000044: Essential documents for the trial should be supplemented or may be reduced where justified (in advance
p.000044: of trial initiation) based on the importance and relevance of the specific documents to the trial.
p.000044:
p.000044:
p.000044:
p.000045: 45
p.000045:
p.000045: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000045:
p.000045: The sponsor should ensure that the investigator has control of and continuous access to the CRF data reported to the
p.000045: sponsor. The sponsor should not have exclusive control of those data.
p.000045: When a copy is used to replace an original document (e.g., source documents, CRF), the copy should fulfill the
p.000045: requirements for certified copies.
p.000045: The investigator/institution should have control of all essential documents and records generated by the
p.000045: investigator/institution before, during, and after the trial.
p.000045:
p.000045: 8.2 Before the Clinical Phase of the Trial Commences
p.000045: During this planning stage the following documents should be generated and should be on file before the trial formally
p.000045: starts
p.000045:
p.000045:
p.000045: Title of Document
p.000045: Purpose
p.000045: Located in Files of
p.000045:
p.000045:
p.000045:
p.000045: 8.2.1
p.000045:
p.000045:
p.000045: 8.2.2
p.000045:
p.000045:
p.000045: 8.2.3
p.000045:
p.000045:
...
p.000045:
p.000045: To document that subjects will be given appropriate written information (content and
p.000045: wording) to support their ability to give fully informed consent
p.000045: Investigator/ Institution
p.000045: X
p.000045:
p.000045:
p.000045: X
p.000045:
p.000045:
p.000045: X
p.000045:
p.000045:
p.000045:
p.000045: X
p.000045: Sponsor
p.000045:
p.000045: X
p.000045:
p.000045:
p.000045: X
p.000045:
p.000045:
p.000045: X
p.000045:
p.000045:
p.000045:
p.000045: X
p.000045:
p.000045:
p.000045:
p.000045:
p.000046: 46
p.000046:
p.000046: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000046:
p.000046:
p.000046: Title of Document
p.000046: Purpose
p.000046: Located in Files of
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046: 8.2.4
p.000046:
p.000046:
p.000046: - ADVERTISEMENT FOR SUBJECT
p.000046: RECRUITMENT (if used)
p.000046:
p.000046: FINANCIAL ASPECTS OF THE TRIAL
p.000046:
p.000046:
p.000046: To document that recruitment measures are appropriate and not coercive
p.000046:
p.000046: To document the financial agreement between the investigator/institution and the sponsor for the trial
p.000046: Investigator/ Institution
p.000046: X X
p.000046: Sponsor
p.000046:
p.000046:
p.000046:
p.000046:
p.000046: X
p.000046:
p.000046:
p.000046: 8.2.5
p.000046:
p.000046: 8.2.6
p.000046: INSURANCE STATEMENT
p.000046: (where required)
p.000046:
p.000046: SIGNED AGREEMENT BETWEEN INVOLVED PARTIES, e.g.:
p.000046: - investigator/institution and sponsor
p.000046: - investigator/institution and CRO
p.000046: - sponsor and CRO
p.000046: - investigator/institution and authority(ies) (where required)
p.000046: To document that compensation to subject(s) for X trial-related injury will be available
p.000046:
p.000046: To document agreements
p.000046:
p.000046: X X
p.000046:
p.000046:
p.000046: X
p.000046: X
p.000046:
p.000046:
p.000046:
p.000046: X X
p.000046: (where required)
p.000046: X X
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000046:
p.000047: 47
p.000047:
p.000047: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000047:
p.000047:
p.000047: Title of Document
p.000047: Purpose
p.000047: Located in Files of
p.000047:
p.000047:
p.000047:
p.000047: 8.2.7
p.000047:
p.000047:
p.000047: DATED, DOCUMENTED APPROVAL/FAVOURABLE OPINION OF INSTITUTIONAL REVIEW BOARD (IRB)
p.000047: /INDEPENDENT ETHICS COMMITTEE (IEC) OF THE FOLLOWING:
p.000047: - protocol and any amendments
p.000047: - CRF (if applicable)
p.000047: - informed consent form(s)
p.000047: - any other written information to be provided to the subject(s)
p.000047: - advertisement for subject recruitment (if used)
p.000047: - subject compensation (if any)
p.000047: - any other documents given approval/ favourable opinion
p.000047:
p.000047:
p.000047: To document that the trial has been subject to IRB/IEC review and given approval/favourable opinion. To
p.000047: identify the version number and date of the document(s)
p.000047: Investigator/ Institution
p.000047: X
p.000047: Sponsor
p.000047:
p.000047: X
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000047:
p.000048: 48
p.000048:
p.000048: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000048:
p.000048:
p.000048:
p.000048:
p.000048: Title of Document
p.000048: Purpose
p.000048: Located in Files of
p.000048:
p.000048:
p.000048:
p.000048: 8.2.8
p.000048:
p.000048:
p.000048:
p.000048: 8.2.9
p.000048:
p.000048:
p.000048:
p.000048:
p.000048: 8.2.10
p.000048:
p.000048:
p.000048:
p.000048: 8.2.11
p.000048:
p.000048:
p.000048: INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE COMPOSITION
p.000048:
p.000048: REGULATORY AUTHORITY(IES) AUTHORISATION/APPROVAL/ NOTIFICATION OF PROTOCOL
p.000048: (where required)
p.000048:
p.000048:
p.000048: CURRICULUM VITAE AND/OR OTHER RELEVANT DOCUMENTS EVIDENCING QUALIFICATIONS OF INVESTIGATOR(S) AND SUB-INVESTIGATOR(S)
p.000048:
p.000048: NORMAL VALUE(S)/RANGE(S) FOR MEDICAL/ LABORATORY/TECHNICAL PROCEDURE(S) AND/OR TEST(S) INCLUDED IN THE PROTOCOL
p.000048:
p.000048:
p.000048: To document that the IRB/IEC is constituted in agreement with GCP
p.000048:
p.000048:
p.000048: To document appropriate authorisation/approval/notification by the regulatory authority(ies) has been obtained prior to
p.000048: initiation of the trial in compliance with the applicable regulatory requirement(s)
p.000048:
p.000048: To document qualifications and eligibility to conduct trial and/or provide medical supervision of subjects
p.000048:
p.000048: To document normal values and/or ranges of the tests
p.000048: Investigator/ Institution
p.000048: X
p.000048:
p.000048:
p.000048:
p.000048: X
p.000048: (where required)
p.000048:
p.000048:
p.000048: X
p.000048:
p.000048:
p.000048:
p.000048: X
p.000048: Sponsor
p.000048:
p.000048: X
p.000048: (where required)
p.000048:
p.000048: X
p.000048: (where required)
p.000048:
p.000048:
p.000048: X
p.000048:
p.000048:
p.000048:
p.000048: X
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000048:
p.000049: 49
p.000049:
p.000049: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000049:
p.000049:
p.000049: Title of Document
p.000049: Purpose
p.000049: Located in Files of
p.000049:
p.000049:
p.000049:
p.000049: 8.2.12
p.000049:
p.000049:
p.000049: MEDICAL/LABORATORY/TECHNICAL PROCEDURES /TESTS
p.000049: - certification or
p.000049: - accreditation or
p.000049: - established quality control and/or external quality assessment or
p.000049: - other validation (where required)
p.000049:
p.000049:
p.000049: To document competence of facility to perform required test(s), and support reliability of results
p.000049: Investigator/ Institution
p.000049: X
p.000049: (where required)
p.000049: Sponsor
p.000049:
p.000049: X
p.000049:
p.000049:
p.000049: 8.2.13
p.000049: SAMPLE OF LABEL(S) ATTACHED TO INVESTIGATIONAL PRODUCT CONTAINER(S)
p.000049: To document compliance with applicable labelling X regulations and
...
p.000052: available
p.000052:
p.000052: To document revisions of these trial related documents that take effect during trial
p.000052: Investigator/ Institution
p.000052: X
p.000052:
p.000052:
p.000052: X
p.000052: Sponsor
p.000052:
p.000052: X
p.000052:
p.000052:
p.000052: X
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000052:
p.000053: 53
p.000053:
p.000053: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000053:
p.000053:
p.000053: Title of Document
p.000053: Purpose
p.000053: Located in Files of
p.000053:
p.000053:
p.000053:
p.000053: 8.3.3
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053: 8.3.4
p.000053:
p.000053:
p.000053:
p.000053: 8.3.5
p.000053:
p.000053:
p.000053: DATED, DOCUMENTED APPROVAL/FAVOURABLE OPINION OF INSTITUTIONAL REVIEW BOARD (IRB)
p.000053: /INDEPENDENT ETHICS COMMITTEE (IEC) OF THE FOLLOWING:
p.000053: - protocol amendment(s)
p.000053: - revision(s) of:
p.000053: - informed consent form
p.000053: - any other written information to be provided to the subject
p.000053: - advertisement for subject recruitment (if used)
p.000053: - any other documents given approval/favourable opinion
p.000053: - continuing review of trial (where required)
p.000053: REGULATORY AUTHORITY(IES) AUTHORISATIONS/APPROVALS/NOTIFIC ATIONS WHERE REQUIRED FOR:
p.000053: - protocol amendment(s) and other documents
p.000053: CURRICULUM VITAE FOR NEW INVESTIGATOR(S) AND/OR SUB- INVESTIGATOR(S)
p.000053:
p.000053:
p.000053: To document that the amendment(s) and/or revision(s) have been subject to IRB/IEC review and were
p.000053: given approval/favourable opinion. To identify the version number and date of the document(s).
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053: To document compliance with applicable regulatory requirements
p.000053:
p.000053:
p.000053: (see 8.2.10)
p.000053: Investigator/ Institution
p.000053: X
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053: X
p.000053: (where required)
p.000053:
p.000053: X
p.000053: Sponsor
p.000053:
p.000053: X
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053: X
p.000053:
p.000053:
p.000053:
p.000053: X
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000053:
p.000054: 54
p.000054:
p.000054: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000054:
p.000054:
p.000054: Title of Document
p.000054: Purpose
p.000054: Located in Files of
p.000054:
p.000054:
p.000054:
p.000054: 8.3.6
p.000054:
p.000054:
p.000054:
p.000054:
p.000054: 8.3.7
p.000054:
p.000054:
p.000054:
p.000054:
p.000054:
p.000054:
p.000054: 8.3.8
p.000054:
p.000054:
p.000054: 8.3.9
p.000054:
p.000054:
p.000054: 8.3.10
p.000054:
p.000054:
...
p.000055: participation of each subject in trial. Also to document direct access permission (see 8.2.3)
p.000055:
p.000055: To document the existence of the subject and substantiate integrity of trial data collected. To include
p.000055: original documents related to the trial, to medical treatment, and history of subject
p.000055:
p.000055: To document that the investigator or authorised member of the investigator’s staff confirms the
p.000055: observations recorded
p.000055:
p.000055: To document all changes/additions or corrections made to CRF after initial data were recorded
p.000055:
p.000055: Notification by originating investigator to sponsor of serious adverse events and related reports in accordance
p.000055: with 4.11
p.000055: X
p.000055:
p.000055:
p.000055:
p.000055: X
p.000055:
p.000055:
p.000055:
p.000055: X
p.000055: (copy)
p.000055:
p.000055: X
p.000055: (copy) X
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055:
p.000055: X
p.000055: (original)
p.000055:
p.000055: X
p.000055: (original) X
p.000055:
p.000055:
p.000056: 56
p.000056:
p.000056: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000056:
p.000056:
p.000056: Title of Document
p.000056: Purpose
p.000056: Located in Files of
p.000056:
p.000056:
p.000056:
p.000056: 8.3.17
p.000056:
p.000056:
p.000056:
p.000056:
p.000056:
p.000056: 8.3.18
p.000056:
p.000056:
p.000056: 8.3.19
p.000056:
p.000056:
p.000056: 8.3.20
p.000056:
p.000056:
p.000056: 8.3.21
p.000056:
p.000056:
p.000056: NOTIFICATION BY SPONSOR AND/OR INVESTIGATOR, WHERE APPLICABLE, TO REGULATORY AUTHORITY(IES) AND IRB(S)/IEC(S) OF
p.000056: UNEXPECTED SERIOUS ADVERSE DRUG REACTIONS AND OF OTHER SAFETY INFORMATION
p.000056:
p.000056: NOTIFICATION BY SPONSOR TO INVESTIGATORS OF SAFETY INFORMATION
p.000056:
p.000056: INTERIM OR ANNUAL REPORTS TO IRB/IEC AND AUTHORITY(IES)
p.000056:
p.000056: SUBJECT SCREENING LOG
p.000056:
p.000056:
p.000056: SUBJECT IDENTIFICATION CODE LIST
p.000056:
p.000056:
p.000056: Notification by sponsor and/or investigator, where applicable, to regulatory authorities and
p.000056: IRB(s)/IEC(s) of unexpected serious adverse drug reactions in accordance with 5.17 and 4.11.1 and of other
p.000056: safety information in accordance with
p.000056: 5.16.2 and 4.11.2
p.000056:
p.000056: Notification by sponsor to investigators of safety information in accordance with 5.16.2
p.000056:
p.000056: Interim or annual reports provided to IRB/IEC in accordance with 4.10 and to authority(ies) in
p.000056: accordance with 5.17.3
p.000056:
p.000056: To document identification of subjects who entered pre-trial screening
p.000056:
p.000056: To document that investigator/institution keeps a confidential list of names of all subjects allocated to trial
p.000056: numbers on enrolling in the trial. Allows investigator/institution to reveal identity of any subject
p.000056: Investigator/ Institution
p.000056: X
p.000056: (where required)
p.000056:
p.000056:
p.000056:
p.000056: X
p.000056:
p.000056:
p.000056: X
p.000056:
p.000056:
p.000056: X
p.000056:
p.000056:
p.000056: X
p.000056: Sponsor
p.000056:
p.000056: X
p.000056:
p.000056:
p.000056:
p.000056:
p.000056:
p.000056: X
p.000056:
p.000056:
p.000056: X
p.000056: (where required)
p.000056:
p.000056: X
p.000056: (where required)
p.000056:
p.000056:
p.000056:
p.000056:
p.000056:
p.000056:
p.000056:
p.000057: 57
p.000057:
p.000057: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000057:
p.000057:
p.000057: Title of Document
p.000057: Purpose
p.000057: Located in Files of
p.000057:
p.000057:
p.000057:
p.000057: 8.3.22
p.000057:
p.000057:
p.000057: SUBJECT ENROLMENT LOG
p.000057:
p.000057:
p.000057: To document chronological enrolment of subjects by trial number
p.000057: Investigator/ Institution
p.000057: X
p.000057: Sponsor
p.000057:
p.000057:
p.000057:
p.000057:
p.000057: 8.3.23
p.000057:
p.000057: 8.3.24
p.000057:
p.000057:
p.000057: 8.3.25
p.000057: INVESTIGATIONAL PRODUCTS ACCOUNTABILITY AT THE SITE
p.000057:
p.000057: SIGNATURE SHEET
p.000057:
p.000057:
p.000057: RECORD OF RETAINED BODY FLUIDS/ TISSUE SAMPLES (IF ANY)
p.000057: To document that investigational product(s) have X X been used according to
p.000057: the protocol
p.000057:
...
p.000058:
p.000058: To document destruction of unused investigational products by sponsor or at site
p.000058: Investigator/ Institution
p.000058: X
p.000058:
p.000058:
p.000058:
p.000058:
p.000058:
p.000058: X
p.000058: (if destroyed at site)
p.000058: Sponsor
p.000058:
p.000058: X
p.000058:
p.000058:
p.000058:
p.000058:
p.000058:
p.000058: X
p.000058:
p.000058:
p.000058:
p.000058: 8.4.3
p.000058:
p.000058:
p.000058:
p.000058: 8.4.4
p.000058:
p.000058: 8.4.5
p.000058:
p.000058: COMPLETED SUBJECT IDENTIFICATION CODE LIST
p.000058:
p.000058:
p.000058: AUDIT CERTIFICATE (if available)
p.000058:
p.000058: FINAL TRIAL CLOSE-OUT MONITORING REPORT
p.000058:
p.000058: To permit identification of all subjects enrolled in X the trial in case follow-up is required. List
p.000058: should
p.000058: be kept in a confidential manner and for agreed upon time
p.000058:
p.000058: To document that audit was performed X
p.000058:
p.000058: To document that all activities required for trial X close-out are
p.000058: completed, and copies of essential
p.000058: documents are held in the appropriate files
p.000058:
p.000058:
p.000058:
p.000058:
p.000059: 59
p.000059:
p.000059: Integrated Addendum to E6(R1): Guideline for Good Clinical Practice
p.000059:
p.000059:
p.000059: Title of Document
p.000059: Purpose
p.000059: Located in Files of
p.000059:
p.000059:
p.000059:
p.000059: 8.4.6
p.000059:
p.000059: 8.4.7
p.000059:
p.000059:
p.000059:
p.000059: 8.4.8
p.000059:
p.000059:
p.000059: TREATMENT ALLOCATION AND DECODING DOCUMENTATION
p.000059:
p.000059: FINAL REPORT BY INVESTIGATOR TO IRB/IEC WHERE REQUIRED, AND WHERE APPLICABLE, TO THE REGULATORY AUTHORITY(IES)
p.000059: CLINICAL STUDY REPORT
p.000059:
p.000059:
p.000059: Returned to sponsor to document any decoding that may have occurred
p.000059:
p.000059: To document completion of the trial
p.000059:
p.000059:
p.000059:
p.000059: To document results and interpretation of trial
p.000059: Investigator/ Institution
p.000059:
p.000059:
p.000059:
p.000059: X
p.000059:
p.000059:
p.000059:
p.000059: X
p.000059: (if applicable)
p.000059: Sponsor
p.000059:
p.000059: X
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059: X
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
p.000059:
...
General/Other / Undue Influence
Searching for indicator undue influence:
(return to top)
p.000009:
p.000009: 3.1.5 The IRB/IEC may request more information than is outlined in paragraph 4.8.10 be given to subjects when, in
p.000009: the judgement of the IRB/IEC, the additional information would add meaningfully to the protection of the rights, safety
p.000009: and/or well-being of the subjects.
p.000009:
p.000009: 3.1.6 When a non-therapeutic trial is to be carried out with the consent of the subject’s legally acceptable
p.000009: representative (see 4.8.12, 4.8.14), the IRB/IEC should determine that the proposed protocol and/or
p.000009: other document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements
p.000009: for such trials.
p.000009:
p.000009:
p.000009:
p.000010: 10
p.000010:
p.000010: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000010:
p.000010: 3.1.7 Where the protocol indicates that prior consent of the trial subject or the subject’s legally acceptable
p.000010: representative is not possible (see 4.8.15), the IRB/IEC should determine that the proposed protocol and/or other
p.000010: document(s) adequately addresses relevant ethical concerns and meets applicable regulatory requirements for such
p.000010: trials (i.e., in emergency situations).
p.000010:
p.000010: 3.1.8 The IRB/IEC should review both the amount and method of payment to subjects to assure that
p.000010: neither presents problems of coercion or undue influence on the trial subjects. Payments to a subject should be
p.000010: prorated and not wholly contingent on completion of the trial by the subject.
p.000010:
p.000010: 3.1.9 The IRB/IEC should ensure that information regarding payment to subjects, including the methods, amounts, and
p.000010: schedule of payment to trial subjects, is set forth in the written informed consent form and any other written
p.000010: information to be provided to subjects. The way payment will be prorated should be specified.
p.000010:
p.000010: 3.2 Composition, Functions and Operations
p.000010:
p.000010: 3.2.1 The IRB/IEC should consist of a reasonable number of members, who collectively have the qualifications and
p.000010: experience to review and evaluate the science, medical aspects, and ethics of the proposed trial. It is recommended
p.000010: that the IRB/IEC should include:
p.000010:
p.000010: (a) At least five members.
p.000010:
p.000010: (b) At least one member whose primary area of interest is in a nonscientific area.
p.000010:
p.000010: (c) At least one member who is independent of the institution/trial site.
p.000010:
p.000010: Only those IRB/IEC members who are independent of the investigator and the sponsor of the trial should vote/provide
p.000010: opinion on a trial-related matter.
p.000010:
p.000010: A list of IRB/IEC members and their qualifications should be maintained.
p.000010:
p.000010: 3.2.2 The IRB/IEC should perform its functions according to written operating procedures, should maintain
p.000010: written records of its activities and minutes of its meetings, and should comply with GCP and with the applicable
p.000010: regulatory requirement(s).
p.000010:
...
General/Other / participants in a control group
Searching for indicator placebo:
(return to top)
p.000002: A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s).
p.000002: Single-blinding usually refers to the subject(s) being unaware, and double- blinding usually refers to the
p.000002: subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the treatment
p.000002: assignment(s).
p.000002: 1.11 Case Report Form (CRF)
p.000002: A printed, optical, or electronic document designed to record all of the protocol required information to
p.000002: be reported to the sponsor on each trial subject.
p.000002: 1.12 Clinical Trial/Study
p.000002: Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other
p.000002: pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an
p.000002: investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an
p.000002: investigational product(s) with the object of ascertaining its safety and/or efficacy. The terms clinical trial
p.000002: and clinical study are synonymous.
p.000002: 1.13 Clinical Trial/Study Report
p.000002: A written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent conducted in
p.000002: human subjects, in which the clinical and statistical description, presentations, and analyses are fully integrated
p.000002: into a single report (see the ICH Guideline for Structure and Content of Clinical Study Reports).
p.000002: 1.14 Comparator (Product)
p.000002: An investigational or marketed product (i.e., active control), or placebo, used as a reference in a clinical trial.
p.000002: 1.15 Compliance (in relation to trials)
p.000002: Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements, and the applicable
p.000002: regulatory requirements.
p.000002: 1.16 Confidentiality
p.000002: Prevention of disclosure, to other than authorized individuals, of a sponsor's proprietary information or of
p.000002: a subject's identity.
p.000002: 1.17 Contract
p.000002: A written, dated, and signed agreement between two or more involved parties that sets out any arrangements on
p.000002: delegation and distribution of tasks and obligations and, if appropriate, on financial matters. The protocol
p.000002: may serve as the basis of a contract.
p.000002: 1.18 Coordinating Committee
p.000002: A committee that a sponsor may organize to coordinate the conduct of a multicentre trial.
p.000002: 1.19 Coordinating Investigator
p.000002: An investigator assigned the responsibility for the coordination of investigators at different centres
p.000002: participating in a multicentre trial.
p.000002:
p.000002:
p.000002:
p.000002:
p.000003: 3
p.000003:
p.000003: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000003:
p.000003: 1.20 Contract Research Organization (CRO)
p.000003: A person or an organization (commercial, academic, or other) contracted by the sponsor to perform one or
p.000003: more of a sponsor's trial-related duties and functions.
p.000003: 1.21 Direct Access
p.000003: Permission to examine, analyze, verify, and reproduce any records and reports that are important to evaluation of a
...
p.000004: 1.29 Inspection
p.000004: The act by a regulatory authority(ies) of conducting an official review of documents, facilities, records, and any
p.000004: other resources that are deemed by the authority(ies) to be related to the clinical trial and that may be located
p.000004: at the site of the trial, at the sponsor's and/or contract research organization’s (CRO’s) facilities,
p.000004: or at other establishments deemed appropriate by the regulatory authority(ies).
p.000004: 1.30 Institution (medical)
p.000004: Any public or private entity or agency or medical or dental facility where clinical trials are
p.000004: conducted.
p.000004: 1.31 Institutional Review Board (IRB)
p.000004: An independent body constituted of medical, scientific, and non-scientific members, whose responsibility is
p.000004: to ensure the protection of the rights, safety and well-being of human subjects involved in a trial by, among
p.000004: other things, reviewing, approving, and providing continuing review of trial protocol and amendments and of the
p.000004: methods and material to be used in obtaining and documenting informed consent of the trial subjects.
p.000004: 1.32 Interim Clinical Trial/Study Report
p.000004: A report of intermediate results and their evaluation based on analyses performed during the course of a
p.000004: trial.
p.000004: 1.33 Investigational Product
p.000004: A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial,
p.000004: including a product with a marketing authorization when used or assembled (formulated or packaged) in a
p.000004: way different from the approved form, or when used for an unapproved indication, or when used to gain further
p.000004: information about an approved use.
p.000004: 1.34 Investigator
p.000004: A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team of
p.000004: individuals at a trial site, the investigator is the responsible leader of the team and may be called the principal
p.000004: investigator. See also Subinvestigator.
p.000004: 1.35 Investigator/Institution
p.000004: An expression meaning "the investigator and/or institution, where required by the applicable regulatory
p.000004: requirements".
p.000004: 1.36 Investigator's Brochure
p.000004: A compilation of the clinical and nonclinical data on the investigational product(s) which is relevant to
p.000004: the study of the investigational product(s) in human subjects (see 7. Investigator’s Brochure).
p.000004: 1.37 Legally Acceptable Representative
p.000004: An individual or juridical or other body authorized under applicable law to consent, on behalf of a prospective
p.000004: subject, to the subject's participation in the clinical trial.
p.000004:
p.000004:
p.000005: 5
p.000005:
p.000005: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000005:
p.000005: 1.38 Monitoring
p.000005: The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded,
p.000005: and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and
...
p.000025: modification(s) of the protocol, written informed consent form and any other written information to be provided
p.000025: to subjects, and/or other procedures, the sponsor should obtain from the investigator/institution a copy
p.000025: of the modification(s) made and the date approval/favourable opinion was given by the IRB/IEC.
p.000025:
p.000025: 5.11.3 The sponsor should obtain from the investigator/institution documentation and dates of any IRB/IEC
p.000025: reapprovals/re-evaluations with favourable opinion, and of any withdrawals or suspensions of approval/favourable
p.000025: opinion.
p.000025:
p.000025: 5.12 Information on Investigational Product(s)
p.000025:
p.000025: 5.12.1 When planning trials, the sponsor should ensure that sufficient safety and efficacy data from nonclinical
p.000025: studies and/or clinical trials are available to support human exposure by the route, at the dosages, for the duration,
p.000025: and in the trial population to be studied.
p.000025:
p.000025: 5.12.2 The sponsor should update the Investigator's Brochure as significant new information becomes
p.000025: available (see 7. Investigator's Brochure).
p.000025:
p.000025:
p.000026: 26
p.000026:
p.000026: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000026:
p.000026: 5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s)
p.000026:
p.000026: 5.13.1 The sponsor should ensure that the investigational product(s) (including active comparator(s)
p.000026: and placebo, if applicable) is characterized as appropriate to the stage of development of the product(s), is
p.000026: manufactured in accordance with any applicable GMP, and is coded and labelled in a manner that protects the blinding,
p.000026: if applicable. In addition, the labelling should comply with applicable regulatory requirement(s).
p.000026:
p.000026: 5.13.2 The sponsor should determine, for the investigational product(s), acceptable storage temperatures,
p.000026: storage conditions (e.g., protection from light), storage times, reconstitution fluids and
p.000026: procedures, and devices for product infusion, if any. The sponsor should inform all involved parties
p.000026: (e.g., monitors, investigators, pharmacists, storage managers) of these determinations.
p.000026:
p.000026: 5.13.3 The investigational product(s) should be packaged to prevent contamination and unacceptable
p.000026: deterioration during transport and storage.
p.000026:
p.000026: 5.13.4 In blinded trials, the coding system for the investigational product(s) should include a mechanism
p.000026: that permits rapid identification of the product(s) in case of a medical emergency, but does not permit
p.000026: undetectable breaks of the blinding.
p.000026:
p.000026: 5.13.5 If significant formulation changes are made in the investigational or comparator product(s)
p.000026: during the course of clinical development, the results of any additional studies of the formulated product(s)
p.000026: (e.g., stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly
...
p.000034: and/or institutions involved in the trial.
p.000034:
p.000034: 6.2 Background Information
p.000034:
p.000034: 6.2.1 Name and description of the investigational product(s).
p.000034:
p.000034: 6.2.2 A summary of findings from nonclinical studies that potentially have clinical significance
p.000034: and from clinical trials that are relevant to the trial.
p.000034:
p.000034: 6.2.3 Summary of the known and potential risks and benefits, if any, to human subjects.
p.000034:
p.000034: 6.2.4 Description of and justification for the route of administration, dosage, dosage regimen, and treatment
p.000034: period(s).
p.000034:
p.000034: 6.2.5 A statement that the trial will be conducted in compliance with the protocol, GCP and the applicable
p.000034: regulatory requirement(s).
p.000034:
p.000034: 6.2.6 Description of the population to be studied.
p.000034:
p.000034: 6.2.7 References to literature and data that are relevant to the trial, and that provide
p.000034: background for the trial.
p.000034:
p.000034: 6.3 Trial Objectives and Purpose
p.000034: A detailed description of the objectives and the purpose of the trial.
p.000034:
p.000034: 6.4 Trial Design
p.000034: The scientific integrity of the trial and the credibility of the data from the trial depend
p.000034: substantially on the trial design. A description of the trial design, should include:
p.000034:
p.000034: 6.4.1 A specific statement of the primary endpoints and the secondary endpoints, if any, to be measured during the
p.000034: trial.
p.000034:
p.000034: 6.4.2 A description of the type/design of trial to be conducted (e.g., double-blind, placebo-
p.000034: controlled, parallel design) and a schematic diagram of trial design, procedures and stages.
p.000034:
p.000034: 6.4.3 A description of the measures taken to minimize/avoid bias, including:
p.000034: (a) Randomization.
p.000034: (b) Blinding.
p.000034:
p.000034: 6.4.4 A description of the trial treatment(s) and the dosage and dosage regimen of the investigational
p.000034: product(s). Also include a description of the dosage form, packaging, and labelling of the investigational product(s).
p.000034:
p.000034: 6.4.5 The expected duration of subject participation, and a description of the sequence and duration of
p.000034: all trial periods, including follow-up, if any.
p.000034:
p.000034: 6.4.6 A description of the "stopping rules" or "discontinuation criteria" for individual subjects, parts of trial
p.000034: and entire trial.
p.000034:
p.000034:
p.000035: 35
p.000035:
p.000035: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000035:
p.000035: 6.4.7 Accountability procedures for the investigational product(s), including the placebo(s) and comparator(s), if
p.000035: any.
p.000035:
p.000035: 6.4.8 Maintenance of trial treatment randomization codes and procedures for breaking codes.
p.000035:
p.000035: 6.4.9 The identification of any data to be recorded directly on the CRFs (i.e., no prior written or electronic
p.000035: record of data), and to be considered to be source data.
p.000035:
p.000035: 6.5 Selection and Withdrawal of Subjects
p.000035:
p.000035: 6.5.1 Subject inclusion criteria.
p.000035:
p.000035: 6.5.2 Subject exclusion criteria.
p.000035:
p.000035: 6.5.3 Subject withdrawal criteria (i.e., terminating investigational product treatment/trial
p.000035: treatment) and procedures specifying:
p.000035: (a) When and how to withdraw subjects from the trial/ investigational product treatment.
p.000035: (b) The type and timing of the data to be collected for withdrawn subjects.
p.000035: (c) Whether and how subjects are to be replaced.
p.000035: (d) The follow-up for subjects withdrawn from investigational product treatment/trial treatment.
p.000035:
p.000035: 6.6 Treatment of Subjects
p.000035:
p.000035: 6.6.1 The treatment(s) to be administered, including the name(s) of all the product(s), the dose(s),
p.000035: the dosing schedule(s), the route/mode(s) of administration, and the treatment period(s), including the
p.000035: follow-up period(s) for subjects for each investigational product treatment/trial treatment group/arm of the trial.
p.000035:
p.000035: 6.6.2 Medication(s)/treatment(s) permitted (including rescue medication) and not permitted before and/or
p.000035: during the trial.
p.000035:
p.000035: 6.6.3 Procedures for monitoring subject compliance.
p.000035:
p.000035: 6.7 Assessment of Efficacy
p.000035:
p.000035: 6.7.1 Specification of the efficacy parameters.
p.000035:
...
Orphaned Trigger Words
p.000020: Sponsors should focus on trial activities essential to ensuring human subject protection and the reliability of trial
p.000020: results. Quality management includes the design of efficient clinical trial protocols and tools and
p.000020: procedures for data collection and processing, as well as the collection of information that is essential to decision
p.000020: making.
p.000020: The methods used to assure and control the quality of the trial should be proportionate to the risks inherent in
p.000020: the trial and the importance of the information collected. The sponsor should ensure that all aspects of the
p.000020: trial are operationally feasible and should avoid unnecessary complexity, procedures, and data collection.
p.000020: Protocols, case report forms, and other operational documents should be clear, concise, and consistent.
p.000020: The quality management system should use a risk-based approach as described below.
p.000020:
p.000020: 5.0.1 Critical Process and Data Identification
p.000020: During protocol development, the sponsor should identify those processes and data that are critical to ensure human
p.000020: subject protection and the reliability of trial results.
p.000020:
p.000020: 5.0.2 Risk Identification
p.000020: The sponsor should identify risks to critical trial processes and data. Risks should be considered at both the system
p.000020: level (e.g., standard operating procedures, computerized systems, personnel) and clinical trial level (e.g., trial
p.000020: design, data collection, informed consent process).
p.000020:
p.000020: 5.0.3 Risk Evaluation
p.000020: The sponsor should evaluate the identified risks, against existing risk controls by considering:
p.000020: (a) The likelihood of errors occurring.
p.000020: (b) The extent to which such errors would be detectable.
p.000020: (c) The impact of such errors on human subject protection and reliability of trial results.
p.000020: 5.0.4 Risk Control
p.000020: The sponsor should decide which risks to reduce and/or which risks to accept. The approach used to
p.000020: reduce risk to an acceptable level should be proportionate to the significance of the risk. Risk reduction
p.000020: activities may be incorporated in protocol design and implementation, monitoring plans, agreements between parties
p.000020: defining roles and responsibilities, systematic safeguards to ensure adherence to standard operating
p.000020: procedures, and training in processes and procedures.
p.000020: Predefined quality tolerance limits should be established, taking into consideration the medical and statistical
p.000020: characteristics of the variables as well as the statistical design of the trial, to identify systematic issues that can
p.000020: impact subject safety or reliability of trial
p.000020:
p.000020:
p.000020:
p.000021: 21
p.000021:
p.000021: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000021:
p.000021: results. Detection of deviations from the predefined quality tolerance limits should trigger an evaluation to
p.000021: determine if action is needed.
p.000021: 5.0.5 Risk Communication
p.000021: The sponsor should document quality management activities. The sponsor should communicate quality management
p.000021: activities to those who are involved in or affected by such activities, to facilitate risk review and continual
p.000021: improvement during clinical trial execution.
p.000021: 5.0.6 Risk Review
p.000021: The sponsor should periodically review risk control measures to ascertain whether the implemented quality management
p.000021: activities remain effective and relevant, taking into account emerging knowledge and experience.
p.000021: 5.0.7 Risk Reporting
...
p.000028: protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).
p.000028:
p.000028: 5.18.2 Selection and Qualifications of Monitors
p.000028: (a) Monitors should be appointed by the sponsor.
p.000028: (b) Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge
p.000028: needed to monitor the trial adequately. A monitor’s qualifications should be documented.
p.000028: (c) Monitors should be thoroughly familiar with the investigational product(s), the protocol, written
p.000028: informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs,
p.000028: GCP, and the applicable regulatory requirement(s).
p.000028:
p.000028: 5.18.3 Extent and Nature of Monitoring
p.000028: The sponsor should ensure that the trials are adequately monitored. The sponsor should determine the appropriate
p.000028: extent and nature of monitoring. The determination of the extent and nature of monitoring should be based on
p.000028: considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. In
p.000028: general there is a need for on-site monitoring, before, during, and after the trial; however in exceptional
p.000028: circumstances the sponsor may determine that central monitoring in conjunction with procedures such as
p.000028: investigators’ training and meetings, and extensive written guidance can assure appropriate conduct of the trial
p.000028: in accordance with GCP. Statistically controlled sampling may be an acceptable method for selecting the data to be
p.000028: verified.
p.000028: ADDENDUM
p.000028: The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The
p.000028: flexibility in the extent and nature of monitoring described in this section is intended to permit
p.000028: varied approaches that improve the effectiveness and efficiency of monitoring. The sponsor may choose on-site
p.000028: monitoring, a combination of on-site and centralized monitoring, or, where justified, centralized monitoring.
p.000028: The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring
p.000028: plan).
p.000028: On-site monitoring is performed at the sites at which the clinical trial is being conducted. Centralized monitoring
p.000028: is a remote evaluation of accumulating data, performed in a timely manner, supported by appropriately
p.000028: qualified and trained persons (e.g., data managers, biostatisticians).
p.000028:
p.000028:
p.000028:
p.000028:
p.000028:
p.000029: 29
p.000029:
p.000029: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000029:
p.000029: Centralized monitoring processes provide additional monitoring capabilities that can complement and reduce
p.000029: the extent and/or frequency of on-site monitoring and help distinguish between reliable data and potentially
p.000029: unreliable data.
p.000029: Review, that may include statistical analyses, of accumulating data from centralized monitoring can be used
p.000029: to:
p.000029: (a) identify missing data, inconsistent data, data outliers, unexpected lack of variability and protocol deviations.
p.000029: (b) examine data trends such as the range, consistency, and variability of data within and across sites.
p.000029: (c) evaluate for systematic or significant errors in data collection and reporting at a site or across sites; or
p.000029: potential data manipulation or data integrity problems.
...
p.000029:
p.000029: 5.18.4 Monitor's Responsibilities
p.000029: The monitor(s) in accordance with the sponsor’s requirements should ensure that the trial is conducted and
p.000029: documented properly by carrying out the following activities when relevant and necessary to the trial and the
p.000029: trial site:
p.000029: (a) Acting as the main line of communication between the sponsor and the investigator.
p.000029: (b) Verifying that the investigator has adequate qualifications and resources (see 4.1, 4.2, 5.6) and
p.000029: remain adequate throughout the trial period, that facilities, including laboratories, equipment, and staff,
p.000029: are adequate to safely and properly conduct the trial and remain adequate throughout the trial period.
p.000029: (c) Verifying, for the investigational product(s):
p.000029: (i) That storage times and conditions are acceptable, and that supplies are sufficient throughout
p.000029: the trial.
p.000029: (ii) That the investigational product(s) are supplied only to subjects who are eligible to receive it and
p.000029: at the protocol specified dose(s).
p.000029: (iii) That subjects are provided with necessary instruction on properly using, handling, storing, and
p.000029: returning the investigational product(s).
p.000029: (iv) That the receipt, use, and return of the investigational product(s) at the trial sites are
p.000029: controlled and documented adequately.
p.000029: (v) That the disposition of unused investigational product(s) at the trial sites complies with applicable
p.000029: regulatory requirement(s) and is in accordance with the sponsor.
p.000029: (d) Verifying that the investigator follows the approved protocol and all approved amendment(s), if any.
p.000029: (e) Verifying that written informed consent was obtained before each subject's participation in the
p.000029: trial.
p.000029: (f) Ensuring that the investigator receives the current Investigator's Brochure, all documents, and all
p.000029: trial supplies needed to conduct the trial properly and to comply with the applicable regulatory requirement(s).
p.000029:
p.000029:
p.000030: 30
p.000030:
p.000030: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000030:
p.000030: (g) Ensuring that the investigator and the investigator's trial staff are adequately informed about
p.000030: the trial.
p.000030: (h) Verifying that the investigator and the investigator's trial staff are performing the specified trial
p.000030: functions, in accordance with the protocol and any other written agreement between the sponsor and
p.000030: the investigator/institution, and have not delegated these functions to unauthorized individuals.
p.000030: (i) Verifying that the investigator is enroling only eligible subjects.
p.000030: (j) Reporting the subject recruitment rate.
p.000030: (k) Verifying that source documents and other trial records are accurate, complete, kept up-to-date and maintained.
p.000030: (l) Verifying that the investigator provides all the required reports, notifications, applications,
p.000030: and submissions, and that these documents are accurate, complete, timely, legible, dated, and identify the
p.000030: trial.
p.000030: (m) Checking the accuracy and completeness of the CRF entries, source documents and other trial-related records against
p.000030: each other. The monitor specifically should verify that:
p.000030: (i) The data required by the protocol are reported accurately on the CRFs and are consistent with the source
p.000030: documents.
...
p.000030:
p.000030: 5.18.5 Monitoring Procedures
p.000030: The monitor(s) should follow the sponsor’s established written SOPs as well as those procedures that are
p.000030: specified by the sponsor for monitoring a specific trial.
p.000030:
p.000030:
p.000031: 31
p.000031:
p.000031: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000031:
p.000031: 5.18.6 Monitoring Report
p.000031: (a) The monitor should submit a written report to the sponsor after each trial-site visit or trial-related
p.000031: communication.
p.000031: (b) Reports should include the date, site, name of the monitor, and name of the investigator or other
p.000031: individual(s) contacted.
p.000031: (c) Reports should include a summary of what the monitor reviewed and the monitor's statements concerning the
p.000031: significant findings/facts, deviations and deficiencies, conclusions, actions taken or to be taken and/or
p.000031: actions recommended to secure compliance.
p.000031: (d) The review and follow-up of the monitoring report with the sponsor should be documented by the
p.000031: sponsor’s designated representative.
p.000031: ADDENDUM
p.000031: (e) Reports of on-site and/or centralized monitoring should be provided to the sponsor (including appropriate
p.000031: management and staff responsible for trial and site oversight) in a timely manner for review and follow up. Results of
p.000031: monitoring activities should be documented in sufficient detail to allow verification of compliance with the
p.000031: monitoring plan. Reporting of centralized monitoring activities should be regular and may be independent from
p.000031: site visits.
p.000031: ADDENDUM
p.000031: 5.18.7 Monitoring Plan
p.000031: The sponsor should develop a monitoring plan that is tailored to the specific human subject protection and
p.000031: data integrity risks of the trial. The plan should describe the monitoring strategy, the monitoring
p.000031: responsibilities of all the parties involved, the various monitoring methods to be used, and the rationale for
p.000031: their use. The plan should also emphasize the monitoring of critical data and processes. Particular attention
p.000031: should be given to those aspects that are not routine clinical practice and that require additional training. The
p.000031: monitoring plan should reference the applicable policies and procedures.
p.000031: 5.19 Audit
p.000031: If or when sponsors perform audits, as part of implementing quality assurance, they should consider:
p.000031:
p.000031: 5.19.1 Purpose
p.000031: The purpose of a sponsor's audit, which is independent of and separate from routine monitoring or
p.000031: quality control functions, should be to evaluate trial conduct and compliance with the protocol,
p.000031: SOPs, GCP, and the applicable regulatory requirements.
p.000031:
p.000031: 5.19.2 Selection and Qualification of Auditors
p.000031: (a) The sponsor should appoint individuals, who are independent of the clinical trials/systems,
p.000031: to conduct audits.
p.000031: (b) The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly.
p.000031: An auditor’s qualifications should be documented.
p.000031:
p.000031:
p.000031:
p.000031:
p.000031:
p.000032: 32
p.000032:
p.000032: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000032:
p.000032:
p.000032: 5.19.3 Auditing Procedures
p.000032: (a) The sponsor should ensure that the auditing of clinical trials/systems is conducted in accordance with the
...
p.000036: Description of ethical considerations relating to the trial.
p.000036:
p.000036: 6.13 Data Handling and Record Keeping
p.000036:
p.000036: 6.14 Financing and Insurance
p.000036: Financing and insurance if not addressed in a separate agreement.
p.000036:
p.000036: 6.15 Publication Policy
p.000036: Publication policy, if not addressed in a separate agreement.
p.000036:
p.000036: 6.16 Supplements
p.000036: (NOTE: Since the protocol and the clinical trial/study report are closely related, further relevant information can
p.000036: be found in the ICH Guideline for Structure and Content of Clinical Study Reports.)
p.000036:
p.000036:
p.000036:
p.000036:
p.000036:
p.000036:
p.000037: 37
p.000037:
p.000037: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000037:
p.000037: 7. INVESTIGATOR’S BROCHURE
p.000037: 7.1 Introduction
p.000037: The Investigator's Brochure (IB) is a compilation of the clinical and nonclinical data on the
p.000037: investigational product(s) that are relevant to the study of the product(s) in human subjects. Its purpose is to
p.000037: provide the investigators and others involved in the trial with the information to facilitate their understanding of
p.000037: the rationale for, and their compliance with, many key features of the protocol, such as the dose, dose
p.000037: frequency/interval, methods of administration: and safety monitoring procedures. The IB also provides insight to
p.000037: support the clinical management of the study subjects during the course of the clinical trial. The information should
p.000037: be presented in a concise, simple, objective, balanced, and non-promotional form that enables a clinician,
p.000037: or potential investigator, to understand it and make his/her own unbiased risk-benefit assessment of the
p.000037: appropriateness of the proposed trial. For this reason, a medically qualified person should generally
p.000037: participate in the editing of an IB, but the contents of the IB should be approved by the disciplines that generated
p.000037: the described data.
p.000037: This guideline delineates the minimum information that should be included in an IB and provides
p.000037: suggestions for its layout. It is expected that the type and extent of information available will vary
p.000037: with the stage of development of the investigational product. If the investigational product is marketed
p.000037: and its pharmacology is widely understood by medical practitioners, an extensive IB may not be necessary. Where
p.000037: permitted by regulatory authorities, a basic product information brochure, package leaflet, or labelling may
p.000037: be an appropriate alternative, provided that it includes current, comprehensive, and detailed information
p.000037: on all aspects of the investigational product that might be of importance to the investigator. If a
p.000037: marketed product is being studied for a new use (i.e., a new indication), an IB specific to that new use should be
p.000037: prepared. The IB should be reviewed at least annually and revised as necessary in compliance with a
p.000037: sponsor's written procedures. More frequent revision may be appropriate depending on the stage of
p.000037: development and the generation of relevant new information. However, in accordance with Good Clinical Practice,
p.000037: relevant new information may be so important that it should be communicated to the investigators, and
p.000037: possibly to the Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) and/or regulatory
p.000037: authorities before it is included in a revised IB.
p.000037: Generally, the sponsor is responsible for ensuring that an up-to-date IB is made available to the investigator(s) and
p.000037: the investigators are responsible for providing the up-to-date IB to the responsible IRBs/IECs. In the
p.000037: case of an investigator sponsored trial, the sponsor-investigator should determine whether a brochure is
p.000037: available from the commercial manufacturer. If the investigational product is provided by the
p.000037: sponsor-investigator, then he or she should provide the necessary information to the trial personnel. In cases
p.000037: where preparation of a formal IB is impractical, the sponsor-investigator should provide, as a substitute,
p.000037: an expanded background information section in the trial protocol that contains the minimum current information
p.000037: described in this guideline.
p.000037:
p.000037: 7.2 General Considerations
p.000037: The IB should include:
p.000037: 7.2.1 Title Page
p.000037: This should provide the sponsor's name, the identity of each investigational product (i.e., research number, chemical
p.000037: or approved generic name, and trade name(s) where legally permissible and desired by the sponsor), and the release
p.000037: date. It is also suggested that an
p.000037:
p.000037:
p.000038: 38
p.000038:
p.000038: Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice
p.000038:
p.000038: edition number, and a reference to the number and date of the edition it supersedes, be provided. An example is given
p.000038: in Appendix 1.
p.000038:
p.000038: 7.2.2 Confidentiality Statement
p.000038: The sponsor may wish to include a statement instructing the investigator/recipients to treat the IB as a
...
Appendix
Indicator List
| Indicator | Vulnerability |
|---|
| access | Access to Social Goods |
| age | Age |
| armed forces | Soldier |
| authority | Relationship to Authority |
| coerce | Presence of Coercion |
| disability | Mentally Disabled |
| drug | Drug Usage |
| education | education |
| embryo | embryo |
| emergency | Public Emergency |
| employees | employees |
| ethnic | Ethnicity |
| fetus | Fetus/Neonate |
| gender | gender |
| hazard | Natural Hazards |
| healthy volunteers | Healthy People |
| homeless | Homeless Persons |
| illness | Physically Disabled |
| impaired | Cognitive Impairment |
| incapable | Mentally Incapacitated |
| incapacity | Incapacitated |
| infant | Infant |
| influence | Drug Usage |
| language | Linguistic Proficiency |
| minor | Youth/Minors |
| minority | Racial Minority |
| nomads | nomad |
| opinion | philosophical differences/differences of opinion |
| party | political affiliation |
| placebo | participants in a control group |
| single | Marital Status |
| substance | Drug Usage |
| terminal | Terminally Ill |
| undue influence | Undue Influence |
| unemployed | Unemployment |
| union | Trade Union Membership |
| vulnerable | vulnerable |
Indicator Peers (Indicators in Same Vulnerability)
| Indicator | Peers |
|---|
| drug | ['influence', 'substance'] |
| influence | ['drug', 'substance'] |
| substance | ['drug', 'influence'] |
Trigger Words
coercion
consent
ethics
protect
protection
risk
volunteer
Applicable Type / Vulnerability / Indicator Overlay for this Input