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pdfE6(R2) Good Clinical
Practice: Integrated
Addendum to ICH E6(R1)
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
March 2018
Procedural
OMB Control No. 0910-0843
Current expiration date available at https://www.reginfo.gov
(Search ICR and enter OMB control number 0910-0843)
See additional PRA statement in section 9 of this guidance.
19400977fnlPRAupdate11-04-22.docx
E6(R2) Good Clinical
Practice: Integrated
Addendum to ICH E6(R1)
Guidance for Industry
Additional copies are available from:
Office of Communications, Division of Drug Information
Center for Drug Evaluation and Research
Food and Drug Administration
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Silver Spring, MD 20993-0002
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Email: [email protected]
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and/or
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Food and Drug Administration
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Phone: 800-835-4709 or 240-402-8010
Email: [email protected]
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
March 2018
Procedural
19400977fnlPRAupdate11-04-22.docx
Contains Nonbinding Recommendations
TABLE OF CONTENTS
INTRODUCTION ................................................................................................................ 1
l.
GLOSSARY ..................................................................................................................... 3
2.
THE PRINCIPLES OF ICH GCP ......................................................................... 11
3.
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS
COMMITTEE (IRB/IEC) ....................................................................................... 12
3.1 Responsibilities ........................................................................................................ 12
3.2 Composition, Functions, and Operations ........................................................... 13
3.3 Procedures ................................................................................................................. 14
3.4 Records ....................................................................................................................... 15
4.
4.l
INVESTIGATOR ....................................................................................................... 15
Investigator’s Qualifications and Agreements .................................................. 15
4.2 Adequate Resources ................................................................................................. 15
4.3 Medical Care of Trial Subjects ............................................................................. 16
4.4 Communication with IRB/IEC ............................................................................. 16
4.5 Compliance with Protocol ...................................................................................... 17
4.6 Investigational Product(s) ...................................................................................... 17
4.7 Randomization Procedures and Unblinding ..................................................... 18
4.8 Informed Consent of Trial Subjects .................................................................... 18
4.9 Records and Reports ............................................................................................... 22
4.10 Progress Reports ...................................................................................................... 23
4.11 Safety Reporting ..................................................................................................... 23
4.12 Premature Termination or Suspension of a Trial ........................................... 23
4.13 Final Report(s) by Investigator ............................................................................ 24
5.
SPONSOR ..................................................................................................................... 24
5.0 Quality Management ............................................................................................... 24
5.l
Quality Assurance and Quality Control ............................................................ 25
5.2 Contract Research Organization (CRO) ........................................................... 26
5.3 Medical Expertise ..................................................................................................... 26
5.4 Trial Design ............................................................................................................... 26
5.5 Trial Management, Data Handling, and Recordkeeping ............................... 27
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5.6 Investigator Selection ............................................................................................... 29
5.7 Allocation of Responsibilities .................................................................................. 29
5.8 Compensation to Subjects and Investigators .................................................... 29
5.9 Financing.................................................................................................................... 30
5.10 Notification/Submission to Regulatory Authority(ies) ..................................... 30
5.11 Confirmation of Review by IRB/IEC ................................................................... 30
5.12 Information on Investigational Product(s) ........................................................ 30
5.13 Manufacturing, Packaging, Labeling, and Coding Investigational
Product(s) ................................................................................................................... 31
5.14 Supplying and Handling Investigational Product(s) ....................................... 31
5.15 Record Access ............................................................................................................ 32
5.16 Safety Information ................................................................................................... 32
5.17 Adverse Drug Reaction Reporting ....................................................................... 33
5.18 Monitoring ................................................................................................................ 33
5.18.1 Purpose ............................................................................................................. 33
5.18.2
Selection and Qualifications of Monitors ...................................................... 33
5.18.3
Extent and Nature of Monitoring .................................................................. 33
5.18.4
Monitor's Responsibilities.............................................................................. 34
5.18.5
Monitoring Procedures ................................................................................. 36
5.18.6
Monitoring Report ......................................................................................... 36
5.18.7
Monitoring Plan .............................................................................................. 37
5.19 Audit ........................................................................................................................... 37
5.19.1 Purpose ........................................................................................................... 37
5.19.2
Selection and Qualification of Auditors ...................................................... 37
5.19.3
Auditing Procedures ...................................................................................... 37
5.20 Noncompliance........................................................................................................... 38
5.21 Premature Termination or Suspension of a Trial ........................................... 38
5.22 Clinical Trial/Study Reports ................................................................................. 38
5.23 Multicenter Trials.................................................................................................... 38
6.
6.l
CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S) .... 39
General Information ............................................................................................... 39
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6.2 Background Information ....................................................................................... 40
6.3 Trial Objectives and Purpose ............................................................................... 40
6.4 Trial Design ............................................................................................................... 40
6.5 Selection and Withdrawal of Subjects ................................................................. 41
6.6 Treatment of Subjects ............................................................................................. 41
6.7 Assessment of Efficacy .............................................................................................. 41
6.8 Assessment of Safety ................................................................................................. 41
6.9 Statistics ..................................................................................................................... 42
6.10 Direct Access to Source Data/Documents ........................................................... 42
6.11 Quality Control and Quality Assurance ........................................................... 42
6.12 Ethics .......................................................................................................................... 42
6.13 Data Handling and Recordkeeping ..................................................................... 42
6.14 Financing and Insurance ....................................................................................... 42
6.1 5 Publication Policy .................................................................................................... 42
6.16 Supplements ............................................................................................................. 43
7.
7.l
INVESTIGATOR'S BROCHURE ......................................................................... 43
Introduction.............................................................................................................. 43
7.2 General Considerations .......................................................................................... 44
7.2.1
Title Page ......................................................................................................... 44
7.2.2
Confidentiality Statement .............................................................................. 45
7.3 Contents of the Investigator's Brochure ............................................................ 45
7.4
7.3.1
Table of Contents ........................................................................................... 45
7.3.2
Summary .......................................................................................................... 45
7.3.3
Introduction ..................................................................................................... 45
7.3.4
Physical, Chemical, and Pharmaceutical Properties and Formulation ... 45
7.3.5
Nonclinical Studies ......................................................................................... 45
7.3.6
Effects in Humans ........................................................................................... 47
7.3.7
Summary of Data and Guidance for the Investigator ................................ 48
APPENDIX l................................................................................................................ 49
7.5 APPENDIX 2 ............................................................................................................. 50
8.
ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL
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TRIAL ........................................................................................................................... 51
8.l
Introduction.............................................................................................................. 51
8.2 Before the Clinical Phase of the Trial Commences ........................................... 52
8.3 During the Clinical Conduct of the Trial ........................................................... 56
8.4
After Completion or Termination of the Trial......................................................... 61
9. PAPERWORK REDUCTION ACT OF 1995 ............................................................... 63
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E6(R2) Good Clinical Practice: Integrated Addendum to ICH
E6(R1)
Guidance for Industry 1
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on
this topic. It does not establish any rights for any person and is not binding on FDA or the public. You
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the
title page.
INTRODUCTION
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for
designing, conducting, recording and reporting trials that involve the participation of human
subjects. Compliance with this standard provides public assurance that the rights, safety, and
well-being of trial subjects are protected, consistent with the principles that have their origin
in the Declaration of Helsinki, and that the clinical trial data are credible.
The objective of this ICH GCP guidance is to provide a unified standard for the European
Union, Japan, and the United States to facilitate the mutual acceptance of clinical data by
the regulatory authorities in these jurisdictions.
The guidance was developed with consideration of the current good clinical practices of the
European Union, Japan, and the United States, as well as those of Australia, Canada, the
Nordic countries, and the World Health Organization.
This guidance should be followed when generating clinical trial data that are intended to be
submitted to regulatory authorities.
The principles established in this guidance may also be applied to other clinical investigations
that may have an impact on the safety and well-being of human subjects.
This guidance was developed within the Expert Working Group (Procedural) of the International Council for
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) (formerly the International
Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) and
has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document has
been endorsed by the ICH Management Committee at Step 4 of the ICH process, November 2016. At Step 4 of the
process, the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan, and the
United States authorities represented at ICH.
1
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ADDENDUM
Since the development of the ICH GCP Guidance, the scale, complexity, and cost of
clinical trials have increased. Evolutions in technology and risk management processes
offer new opportunities to increase efficiency and focus on relevant activities. When the
original ICH E6(R1) text was prepared, clinical trials were performed in a largely paperbased process. Advances in use of electronic data recording and reporting facilitate
implementation of other approaches. For example, centralized monitoring can now offer a
greater advantage, to a broader range of trials than is suggested in the original text.
Therefore, this guidance has been amended to encourage implementation of improved
and more efficient approaches to clinical trial design, conduct, oversight, recording, and
reporting while continuing to ensure human subject protection and reliability of trial
results. Standards regarding electronic records and essential documents intended to increase
clinical trial quality and efficiency have also been updated.
This guidance should be read in conjunction with other ICH guidances relevant to the
conduct of clinical trials (e.g., E2A (clinical safety data management), E3 (clinical study
reporting), E7 (geriatric populations), E8 (general considerations for clinical trials), E9
(statistical principles), and E11 (pediatric populations)).
This ICH GCP Guidance Integrated Addendum provides a unified standard for the
European Union, Japan, the United States, Canada, and Switzerland to facilitate the mutual
acceptance of data from clinical trials by the regulatory authorities in these jurisdictions. In
the event of any conflict between the E6(R1) text and the E6(R2) addendum text, the
E6(R2) addendum text should take priority.
In general, FDA’s guidance documents do not establish legally enforceable responsibilities.
Instead, guidances describe the Agency’s current thinking on a topic and should be viewed
only as recommendations, unless specific regulatory or statutory requirements are cited. The
use of the word should in Agency guidances means that something is suggested or
recommended, but not required.
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Contains Nonbinding Recommendations
l.
GLOSSARY
1.1
Adverse Drug Reaction (ADR)
In the preapproval clinical experience with a new medicinal product or its new usages,
particularly as the therapeutic dose(s) may not be established, all noxious and unintended
responses to a medicinal product related to any dose should be considered adverse drug
reactions. The phrase “responses to a medicinal product” means that a causal relationship
between a medicinal product and an adverse event is at least a reasonable possibility, i.e., the
relationship cannot be ruled out.
Regarding marketed medicinal products: A response to a drug which is noxious and unintended
and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of
diseases or for modification of physiological function (see the ICH Guideline for Clinical Safety
Data Management: Definitions and Standards for Expedited Reporting).
1.2
Adverse Event (AE)
Any untoward medical occurrence in a patient or clinical investigation subject administered a
pharmaceutical product and which does not necessarily have a causal relationship with this
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal
laboratory finding), symptom, or disease temporally associated with the use of a medicinal
(investigational) product, whether or not related to the medicinal (investigational) product (see
the ICH Guidance for Clinical Safety Data Management: Definitions and Standards for
Expedited Reporting).
1.3
Amendment (to the protocol)
See Protocol Amendment.
1.4
Applicable Regulatory Requirement(s)
Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products.
1.5
Approval (in relation to institutional review boards (IRBs))
The affirmative decision of the IRB that the clinical trial has been reviewed and may be
conducted at the institution site within the constraints set forth by the IRB, the institution, good
clinical practice (GCP), and the applicable regulatory requirements.
1.6
Audit
A systematic and independent examination of trial-related activities and documents to determine
whether the evaluated trial-related activities were conducted, and the data were recorded,
analyzed, and accurately reported according to the protocol, sponsor's standard operating
procedures (SOPs), good clinical practice (GCP), and the applicable regulatory requirement(s).
1.7
Audit Certificate
A declaration of confirmation by the auditor that an audit has taken place.
1.8
Audit Report
A written evaluation by the sponsor’s auditor of the results of the audit.
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1.9
Audit Trail
Documentation that allows reconstruction of the course of events.
1.10 Blinding/Masking
A procedure in which one or more parties to the trial are kept unaware of the treatment
assignment(s). Single-blinding usually refers to the subject(s) being unaware, and doubleblinding usually refers to the subject(s), investigator(s), monitor, and, in some cases, data
analyst(s) being unaware of the treatment assignment(s).
1.11 Case Report Form (CRF)
A printed, optical, or electronic document designed to record all of the protocol required
information to be reported to the sponsor on each trial subject.
1.12 Clinical Trial/Study
Any investigation in human subjects intended to discover or verify the clinical, pharmacological
and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any
adverse reactions to an investigational product(s), and/or to study absorption, distribution,
metabolism, and excretion of an investigational product(s) with the object of ascertaining its
safety and/or efficacy. The terms clinical trial and clinical study are synonymous.
1.13 Clinical Trial/Study Report
A written description of a trial/study of any therapeutic, prophylactic, or diagnostic agent
conducted in human subjects, in which the clinical and statistical description, presentations, and
analyses are fully integrated into a single report (see the ICH Guidance for Structure and Content
of Clinical Study Reports).
1.14 Comparator (Product)
An investigational or marketed product (i.e., active control), or placebo, used as a reference in a
clinical trial.
1.15 Compliance (in relation to trials)
Adherence to all the trial-related requirements, good clinical practice (GCP) requirements, and
the applicable regulatory requirements.
1.16 Confidentiality
Prevention of disclosure, to other than authorized individuals, of a sponsor’s proprietary
information or of a subject’s identity.
1.17 Contract
A written, dated, and signed agreement between two or more involved parties that sets out any
arrangements on delegation and distribution of tasks and obligations and, if appropriate, on
financial matters. The protocol may serve as the basis of a contract.
1.18 Coordinating Committee
A committee that a sponsor may organize to coordinate the conduct of a multicenter trial.
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Contains Nonbinding Recommendations
1.19 Coordinating Investigator
An investigator assigned the responsibility for the coordination of investigators at different
centers participating in a multicenter trial.
l.20 Contract Research Organization (CRO)
A person or an organization (commercial, academic, or other) contracted by the sponsor to
perform one or more of a sponsor's trial-related duties and functions.
l.2l
Direct Access
Permission to examine, analyze, verify, and reproduce any records and reports that are important
to evaluation of a clinical trial. Any party (e.g., domestic and foreign regulatory authorities,
sponsor’s monitors, and auditors) with direct access should take all reasonable precautions
within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality
of subjects’ identities and sponsor’s proprietary information.
1.22 Documentation
All records, in any form (including, but not limited to, written, electronic, magnetic, and optical
records, and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct,
and/or results of a trial, the factors affecting a trial, and the actions taken.
1.23 Essential Documents
Documents that individually and collectively permit evaluation of the conduct of a study and the
quality of the data produced (see section 8. “Essential Documents for the Conduct of a Clinical
Trial”).
1.24 Good Clinical Practice (GCP)
A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, and
reporting of clinical trials that provides assurance that the data and reported results are credible
and accurate, and that the rights, integrity, and confidentiality of trial subjects are protected.
1.25 Independent Data Monitoring Committee (IDMC) (Data and Safety Monitoring
Board, Monitoring Committee, Data Monitoring Committee)
An independent data monitoring committee that may be established by the sponsor to assess at
intervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and to
recommend to the sponsor whether to continue, modify, or stop a trial.
1.26 Impartial Witness
A person, who is independent of the trial, who cannot be unfairly influenced by people involved
with the trial, who attends the informed consent process if the subject or the subject’s legally
acceptable representative cannot read, and who reads the informed consent form and any other
written information supplied to the subject.
1.27 Independent Ethics Committee (IEC)
An independent body (a review board or a committee, institutional, regional, national, or
supranational), constituted of medical professionals and non-medical members, whose
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responsibility it is to ensure the protection of the rights, safety and well-being of human subjects
involved in a trial and to provide public assurance of that protection, by, among other things,
reviewing and approving/providing favorable opinion on the trial protocol, the suitability of the
investigator(s), facilities, and the methods and material to be used in obtaining and documenting
informed consent of the trial subjects.
The legal status, composition, function, operations and regulatory requirements pertaining to
Independent Ethics Committees may differ among countries, but should allow the Independent
Ethics Committee to act in agreement with GCP as described in this guidance.
1.28 Informed Consent
A process by which a subject voluntarily confirms his or her willingness to participate in a
particular trial, after having been informed of all aspects of the trial that are relevant to the
subject’s decision to participate. Informed consent is documented by means of a written, signed,
and dated informed consent form.
1.29 Inspection
The act by a regulatory authority(ies) of conducting an official review of documents, facilities,
records, and any other resources that are deemed by the authority(ies) to be related to the clinical
trial and that may be located at the site of the trial, at the sponsor’s and/or contract research
organization’s (CROs) facilities, or at other establishments deemed appropriate by the regulatory
authority(ies).
1.30 Institution (medical)
Any public or private entity or agency or medical or dental facility where clinical trials are
conducted.
l.31 Institutional Review Board (IRB)
An independent body constituted of medical, scientific, and nonscientific members, whose
responsibility is to ensure the protection of the rights, safety and well-being of human subjects
involved in a trial by, among other things, reviewing, approving, and providing continuing
review of trial protocols and amendments and of the methods and material to be used in
obtaining and documenting informed consent of the trial subjects.
1.32 Interim Clinical Trial/Study Report
A report of intermediate results and their evaluation based on analyses performed during the
course of a trial.
1.33 Investigational Product
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a
clinical trial, including a product with a marketing authorization when used or assembled
(formulated or packaged) in a way different from the approved form, or when used for an
unapproved indication, or when used to gain further information about an approved use.
1.34 Investigator
A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a
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Contains Nonbinding Recommendations
team of individuals at a trial site, the investigator is the responsible leader of the team and may
be called the principal investigator. (See also Subinvestigator.)
1.35 Investigator/Institution
An expression meaning “the investigator and/or institution, where required by the applicable
regulatory requirements.”
1.36 Investigator’s Brochure
A compilation of the clinical and nonclinical data on the investigational product(s) that is
relevant to the study of the investigational product(s) in human subjects (see section 7.
“Investigator’s Brochure”).
1.37 Legally Acceptable Representative
An individual or juridical or other body authorized under applicable law to consent, on behalf of
a prospective subject, to the subject’s participation in the clinical trial.
1.38 Monitoring
The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted,
recorded, and reported in accordance with the protocol, standard operating procedures (SOPs),
GCP, and the applicable regulatory requirement(s).
1.39 Monitoring Report
A written report from the monitor to the sponsor after each site visit and/or other trial-related
communication according to the sponsor’s SOPs.
1.40 Multicenter Trial
A clinical trial conducted according to a single protocol but at more than one site, and therefore,
carried out by more than one investigator.
1.41 Nonclinical Study
Biomedical studies not performed on human subjects.
1.42 Opinion (in relation to Independent Ethics Committee)
The judgment and/or the advice provided by an Independent Ethics Committee (IEC).
1.43 Original Medical Record
See Source Documents.
1.44 Protocol
A document that describes the objective(s), design, methodology, statistical considerations, and
organization of a trial. The protocol usually also gives the background and rationale for the trial,
but these could be provided in other protocol referenced documents. Throughout the ICH GCP
Guidance, the term protocol refers to protocol and protocol amendments.
1.45 Protocol Amendment
A written description of a change(s) to or formal clarification of a protocol.
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1.46 Quality Assurance (QA)
All those planned and systematic actions that are established to ensure that the trial is performed
and the data are generated, documented (recorded), and reported in compliance with GCP and
the applicable regulatory requirement(s).
1.47 Quality Control (QC)
The operational techniques and activities undertaken within the quality assurance system to
verify that the requirements for quality of the trial-related activities have been fulfilled.
1.48 Randomization
The process of assigning trial subjects to treatment or control groups using an element of chance
to determine the assignments in order to reduce bias.
1.49 Regulatory Authorities
Bodies having the power to regulate. In the ICH GCP guidance, the expression “Regulatory
Authorities” includes the authorities that review submitted clinical data and those that conduct
inspections (see 1.29). These bodies are sometimes referred to as competent authorities.
1.50 Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)
Any untoward medical occurrence that at any dose:
-
Results in death,
Is life-threatening,
Requires inpatient hospitalization or prolongation of existing hospitalization,
Results in persistent or significant disability/incapacity, or
Is a congenital anomaly/birth defect.
(See the ICH guidance for Clinical Safety Data Management: Definitions and Standards for
Expedited Reporting.)
1.51 Source Data
All information in original records and certified copies of original records of clinical findings,
observations, or other activities in a clinical trial necessary for the reconstruction and evaluation
of the trial. Source data are contained in source documents (original records or certified copies).
1.52 Source Document
Original documents, data, and records (e.g., hospital records, clinical and office charts,
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing
records, recorded data from automated instruments, copies or transcriptions certified after
verification as being accurate copies, microfiches, photographic negatives, microfilm or
magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at
medico-technical departments involved in the clinical trial).
1.53 Sponsor
An individual, company, institution, or organization that takes responsibility for the initiation,
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management, and/or financing of a clinical trial.
1.54 Sponsor-Investigator
An individual who both initiates and conducts, alone or with others, a clinical trial, and under
whose immediate direction the investigational product is administered to, dispensed to, or used
by a subject. The term does not include any person other than an individual (e.g., it does not
include a corporation or an agency). The obligations of a sponsor-investigator include both those
of a sponsor and those of an investigator.
1.55 Standard Operating Procedures (SOPs)
Detailed, written instructions to achieve uniformity of the performance of a specific function.
1.56 Subinvestigator
Any individual member of the clinical trial team designated and supervised by the investigator at
a trial site to perform critical trial-related procedures and/or to make important trial-related
decisions (e.g., associates, residents, research fellows). See also Investigator.
1.57 Subject/Trial Subject
An individual who participates in a clinical trial, either as a recipient of the investigational
product(s) or as a control.
1.58 Subject Identification Code
A unique identifier assigned by the investigator to each trial subject to protect the subject’s
identity and used in lieu of the subject’s name when the investigator reports adverse events
and/or other trial-related data.
1.59 Trial Site
The location(s) where trial-related activities are actually conducted.
1.60 Unexpected Adverse Drug Reaction
An adverse reaction, the nature or severity of which is not consistent with the applicable product
information (e.g., Investigator’s Brochure for an unapproved investigational product or package
insert/summary of product characteristics for an approved product). (See the ICH Guidance for
Clinical Safety Data Management: Definitions and Standards for Expedited Reporting.)
1.61 Vulnerable Subjects
Individuals whose willingness to volunteer in a clinical trial may be unduly influenced by the
expectation, whether justified or not, of benefits associated with participation, or of a retaliatory
response from senior members of a hierarchy in case of refusal to participate. Examples are
members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing
students, subordinate hospital and laboratory personnel, employees of the pharmaceutical
industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects
include patients with incurable diseases, persons in nursing homes, unemployed or impoverished
persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads,
refugees, minors, and those incapable of giving consent.
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1.62 Well-being (of the trial subjects)
The physical and mental integrity of the subjects participating in a clinical trial.
ADDENDUM
1.63 Certified Copy
A copy (irrespective of the type of media used) of the original record that has been verified
(i.e., by a dated signature or by generation through a validated process) to have the same
information, including data that describe the context, content, and structure, as the original.
1.64 Monitoring Plan
A document that describes the strategy, methods, responsibilities, and requirements for
monitoring the trial.
1.65 Validation of Computerized Systems
A process of establishing and documenting that the specified requirements of a computerized
system can be consistently fulfilled from design until decommissioning of the system or
transition to a new system. The approach to validation should be based on a risk assessment
that takes into consideration the intended use of the system and the potential of the system to
affect human subject protection and reliability of trial results.
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2.
THE PRINCIPLES OF ICH GCP
2.l
Clinical trials should be conducted in accordance with the ethical principles that
have their origin in the Declaration of Helsinki, and that are consistent with GCP
and the applicable regulatory requirement(s).
2.2
Before a trial is initiated, foreseeable risks and inconveniences should be weighed
against the anticipated benefit for the individual trial subject and society. A trial should
be initiated and continued only if the anticipated benefits justify the risks.
2.3
The rights, safety, and well-being of the trial subjects are the most important
considerations and should prevail over interests of science and society.
2.4
The available nonclinical and clinical information on an investigational product
should be adequate to support the proposed clinical trial.
2.5
Clinical trials should be scientifically sound, and described in a clear, detailed protocol.
2.6
A trial should be conducted in compliance with the protocol that has received prior
institutional review board (IRB)/independent ethics committee (IEC)
approval/favorable opinion.
2.7
The medical care given to, and medical decisions made on behalf of, subjects
should always be the responsibility of a qualified physician or, when appropriate, of
a qualified dentist.
2.8
Each individual involved in conducting a trial should be qualified by education,
training, and experience to perform his or her respective task(s).
2.9
Freely given informed consent should be obtained from every subject prior to
clinical trial participation.
2.10
All clinical trial information should be recorded, handled, and stored in a way that
allows its accurate reporting, interpretation, and verification.
ADDENDUM
This principle applies to all records referenced in this guidance, irrespective of the type of
media used.
2.11 The confidentiality of records that could identify subjects should be protected,
respecting the privacy and confidentiality rules in accordance with the applicable regulatory
requirement(s).
2.12 Investigational products should be manufactured, handled, and stored in accordance
with applicable good manufacturing practice (GMP). They should be used in accordance
with the approved protocol.
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2.13 Systems with procedures that assure the quality of every aspect of the trial should
be implemented.
ADDENDUM
Aspects of the trial that are essential to ensure human subject protection and reliability of trial
results should be the focus of such systems.
3.
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS
COMMITTEE (IRB/IEC)
3.1
Responsibilities
3.1.1
An IRB/IEC should safeguard the rights, safety, and well-being of all trial
subjects. Special attention should be paid to trials that may include vulnerable
subjects.
3.1.2
The IRB/IEC should obtain the following documents:
Trial protocol(s)/amendment(s), written informed consent form(s) and consent form
updates that the investigator proposes for use in the trial, subject recruitment
procedures (e.g., advertisements), written information to be provided to subjects,
Investigator’s Brochure (IB), available safety information, information about
payments and compensation available to subjects, the investigator’s current curriculum
vitae and/or other documentation evidencing qualifications, and any other
documents that the IRB/IEC may need to fulfil its responsibilities.
The IRB/IEC should review a proposed clinical trial within a reasonable time and
document its views in writing, clearly identifying the trial, the documents reviewed
and the dates for the following:
- Approval/favorable opinion;
- Modifications required prior to its approval/favorable opinion;
- Disapproval/negative opinion; and
- Termination/suspension of any prior approval/favorable opinion.
3.1.3
The IRB/IEC should consider the qualifications of the investigator for the proposed
trial, as documented by a current curriculum vitae and/or by any other relevant
documentation the IRB/IEC requests.
3.1.4
The IRB/IEC should conduct continuing review of each ongoing trial at intervals
appropriate to the degree of risk to human subjects, but at least once per year.
3.1.5
The IRB/IEC may request more information than is outlined in paragraph 4.8.10 be
given to subjects when, in the judgment of the IRB/IEC, the additional information
would add meaningfully to the protection of the rights, safety, and/or well-being of
the subjects.
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3.1.6
When a nontherapeutic trial is to be carried out with the consent of the subject’s
legally acceptable representative (see sections 4.8.12, 4.8.14), the IRB/IEC should
determine that the proposed protocol and/or other document(s) adequately addresses
relevant ethical concerns and meets applicable regulatory requirements for such trials.
3.1.7
Where the protocol indicates that prior consent of the trial subject or the subject’s
legally acceptable representative is not possible (see section 4.8.15), the IRB/IEC
should determine that the proposed protocol and/or other document(s) adequately
addresses relevant ethical concerns and meets applicable regulatory requirements for
such trials (i.e., in emergency situations).
3.1.8
The IRB/IEC should review both the amount and method of payment to subjects to
assure that neither presents problems of coercion or undue influence on the trial
subjects. Payments to a subject should be prorated and not wholly contingent on
completion of the trial by the subject.
3.1.9
The IRB/IEC should ensure that information regarding payment to subjects, including
the methods, amounts, and schedule of payment to trial subjects, is set forth in the
written informed consent form and any other written information to be provided to
subjects. The way payment will be prorated should be specified.
3.2
Composition, Functions, and Operations
3.2.1
The IRB/IEC should consist of a reasonable number of members, who collectively
have the qualifications and experience to review and evaluate the science, medical
aspects, and ethics of the proposed trial. It is recommended that the IRB/IEC should
include:
(a) At least five members.
(b) At least one member whose primary area of interest is in a nonscientific area.
(c) At least one member who is independent of the institution/trial site.
Only those IRB/IEC members who are independent of the investigator and the sponsor
of the trial should vote/provide opinion on a trial-related matter.
A list of IRB/IEC members and their qualifications should be maintained.
3.2.2
The IRB/IEC should perform its functions according to written operating procedures,
should maintain written records of its activities and minutes of its meetings, and
should comply with GCP and with the applicable regulatory requirement(s).
3.2.3
An IRB/IEC should make its decisions at announced meetings at which at least a
quorum, as stipulated in its written operating procedures, is present.
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3.2.4
Only members who participate in the IRB/IEC review and discussion should
vote/provide their opinion and/or advice.
3.2.5
The investigator may provide information on any aspect of the trial, but should not
participate in the deliberations of the IRB/IEC or in the vote/opinion of the IRB/IEC.
3.2.6
An IRB/IEC may invite nonmembers with expertise in special areas for assistance.
3.3
Procedures
The IRB/IEC should establish, document in writing, and follow its procedures, which
should include:
3.3.1
Determining its composition (names and qualifications of the members) and the
authority under which it is established.
3.3.2
Scheduling, notifying its members of, and conducting its meetings.
3.3.3
Conducting initial and continuing review of trials.
3.3.4
Determining the frequency of continuing review, as appropriate.
3.3.5
Providing, according to the applicable regulatory requirements, expedited review and
approval/favorable opinion of minor change(s) in ongoing trials that have the
approval/favorable opinion of the IRB/IEC.
3.3.6
Specifying that no subject should be admitted to a trial before the IRB/IEC issues
its written approval/favorable opinion of the trial.
3.3.7
Specifying that no deviations from, or changes of, the protocol should be initiated
without prior written IRB/IEC approval/favorable opinion of an appropriate
amendment, except when necessary to eliminate immediate hazards to the subjects
or when the change(s) involves only logistical or administrative aspects of the trial
(e.g., change of monitor(s), telephone number(s)) (see section 4.5.2).
3.3.8
Specifying that the investigator should promptly report to the IRB/IEC:
(a) Deviations from, or changes of, the protocol to eliminate immediate hazards to
the trial subjects (see sections 3.3.7, 4.5.2, 4.5.4).
(b) Changes increasing the risk to subjects and/or affecting significantly the conduct
of the trial (see section 4.10.2).
(c) All adverse drug reactions (ADRs) that are both serious and unexpected.
(d) New information that may affect adversely the safety of the subjects or the
conduct of the trial.
3.3.9
Ensuring that the IRB/IEC promptly notify in writing the investigator/institution
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concerning:
(a) Its trial-related decisions/opinions.
(b) The reasons for its decisions/opinions.
(c) Procedures for appeal of its decisions/opinions.
3.4
Records
The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists,
lists of occupations/affiliations of members, submitted documents, minutes of meetings, and
correspondence) for a period of at least 3 years after completion of the trial and make
them available upon request from the regulatory authority(ies).
The IRB/IEC may be asked by investigators, sponsors or regulatory authorities to provide
its written procedures and membership lists.
4.
INVESTIGATOR
4.l
Investigator’s Qualifications and Agreements
4.1.1
The investigator(s) should be qualified by education, training, and experience to
assume responsibility for the proper conduct of the trial, should meet all the
qualifications specified by the applicable regulatory requirement(s), and should
provide evidence of such qualifications through up-to-date curriculum vitae and/or
other relevant documentation requested by the sponsor, the IRB/IEC, and/or the
regulatory authority(ies).
4.l.2
The investigator should be thoroughly familiar with the appropriate use of the
investigational product(s), as described in the protocol, in the current Investigator’s
Brochure, in the product information, and in other information sources provided by
the sponsor.
4.l.3
The investigator should be aware of, and should comply with, GCP and the
applicable regulatory requirements.
4.l.4
The investigator/institution should permit monitoring and auditing by the sponsor,
and inspection by the appropriate regulatory authority(ies).
4.l.5
The investigator should maintain a list of appropriately qualified persons to whom
the investigator has delegated significant trial-related duties.
4.2
Adequate Resources
4.2.1
The investigator should be able to demonstrate (e.g., based on retrospective data) a
potential for recruiting the required number of suitable subjects within the agreed
recruitment period.
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4.2.2
The investigator should have sufficient time to properly conduct and complete the
trial within the agreed trial period.
4.2.3
The investigator should have available an adequate number of qualified staff and
adequate facilities for the foreseen duration of the trial to conduct the trial properly
and safely.
4.2.4
The investigator should ensure that all persons assisting with the trial are
adequately informed about the protocol, the investigational product(s), and their trialrelated duties and functions.
ADDENDUM
4.2.5
The investigator is responsible for supervising any individual or party to whom the
investigator delegates trial-related duties and functions conducted at the trial site.
4.2.6
If the investigator/institution retains the services of any individual or party to
perform trial-related duties and functions, the investigator/institution should ensure this
individual or party is qualified to perform those trial-related duties and functions and
should implement procedures to ensure the integrity of the trial-related duties and
functions performed and any data generated.
4.3
Medical Care of Trial Subjects
4.3.1
A qualified physician (or dentist, when appropriate), who is an investigator or a
subinvestigator for the trial, should be responsible for all trial-related medical (or
dental) decisions.
4.3.2
During and following a subject’s participation in a trial, the investigator/institution
should ensure that adequate medical care is provided to a subject for any adverse
events, including clinically significant laboratory values, related to the trial. The
investigator/institution should inform a subject when medical care is needed for
intercurrent illness(es) of which the investigator becomes aware.
4.3.3
It is recommended that the investigator inform the subject’s primary physician about
the subject’s participation in the trial if the subject has a primary physician and if the
subject agrees to the primary physician being informed.
4.3.4
Although a subject is not obliged to give his/her reason(s) for withdrawing
prematurely from a trial, the investigator should make a reasonable effort to ascertain
the reason(s), while fully respecting the subject’s rights.
4.4
Communication with IRB/IEC
4.4.1
Before initiating a trial, the investigator/institution should have written and dated
approval/favorable opinion from the IRB/IEC for the trial protocol, written informed
consent form, consent form updates, subject recruitment procedures (e.g.,
advertisements), and any other written information to be provided to subjects.
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4.4.2
As part of the investigator’s/institution’s written application to the IRB/IEC, the
investigator/institution should provide the IRB/IEC with a current copy of the
Investigator’s Brochure. If the Investigator’s Brochure is updated during the trial, the
investigator/institution should supply a copy of the updated Investigator’s Brochure
to the IRB/IEC.
4.4.3
During the trial the investigator/institution should provide to the IRB/IEC all
documents subject to review.
4.5
Compliance with Protocol
4.5.1
The investigator/institution should conduct the trial in compliance with the protocol
agreed to by the sponsor and, if required, by the regulatory authority(ies), and which
was given approval/favorable opinion by the IRB/IEC. The investigator/institution
and the sponsor should sign the protocol, or an alternative contract, to confirm
agreement.
4.5.2
The investigator should not implement any deviation from, or changes of, the
protocol without agreement by the sponsor and prior review and documented
approval/favorable opinion from the IRB/IEC of an amendment, except where
necessary to eliminate an immediate hazard(s) to trial subjects, or when the
change(s) involves only logistical or administrative aspects of the trial (e.g., change
in monitor(s), change of telephone number(s)).
4.5.3
The investigator, or person designated by the investigator, should document and
explain any deviation from the approved protocol.
4.5.4
The investigator may implement a deviation from, or a change in, the protocol to
eliminate an immediate hazard(s) to trial subjects without prior IRB/IEC
approval/favorable opinion. As soon as possible, the implemented deviation or
change, the reasons for it, and, if appropriate, the proposed protocol amendment(s)
should be submitted:
(a) To the IRB/IEC for review and approval/favorable opinion;
(b) To the sponsor for agreement and, if required;
(c) To the regulatory authority(ies).
4.6
Investigational Product(s)
4.6.1
Responsibility for investigational product(s) accountability at the trial site(s) rests
with the investigator/institution.
4.6.2
Where allowed/required, the investigator/institution may/should assign some or all of
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the investigator’s/institution’s duties for investigational product(s) accountability at
the trial site(s) to an appropriate pharmacist or another appropriate individual who
is under the supervision of the investigator/institution.
4.6.3
The investigator/institution and/or a pharmacist or other appropriate individual, who
is designated by the investigator/institution, should maintain records of the product’s
delivery to the trial site, the inventory at the site, the use by each subject, and the
return to the sponsor or alternative disposition of unused product(s). These records
should include dates, quantities, batch/serial numbers, expiration dates (if
applicable), and the unique code numbers assigned to the investigational product(s)
and trial subjects. Investigators should maintain records that document adequately
that the subjects were provided the doses specified by the protocol and reconcile all
investigational product(s) received from the sponsor.
4.6.4
The investigational product(s) should be stored as specified by the sponsor (see
sections 5.13.2 and 5.14.3) and in accordance with applicable regulatory requirement(s).
4.6.5
The investigator should ensure that the investigational product(s) are used only in
accordance with the approved protocol.
4.6.6
The investigator, or a person designated by the investigator/institution, should explain
the correct use of the investigational product(s) to each subject and should check, at
intervals appropriate for the trial, that each subject is following the instructions
properly.
4.7
Randomization Procedures and Unblinding
The investigator should follow the trial’s randomization procedures, if any, and should ensure
that the code is broken only in accordance with the protocol. If the trial is blinded, the
investigator should promptly document and explain to the sponsor any premature unblinding
(e.g., accidental unblinding, unblinding due to a serious adverse event) of the investigational
product(s).
4.8
Informed Consent of Trial Subjects
4.8.1
In obtaining and documenting informed consent, the investigator should comply with
the applicable regulatory requirement(s), and should adhere to GCP and to the ethical
principles that have their origin in the Declaration of Helsinki. Prior to the beginning
of the trial, the investigator should have the IRB/IEC’s written approval/favorable
opinion of the written informed consent form and any other written information to be
provided to subjects.
4.8.2
The written informed consent form and any other written information to be provided
to subjects should be revised whenever important new information becomes available
that may be relevant to the subject’s consent. Any revised written informed consent
form, and written information should receive the IRB/IEC’s approval/favorable
opinion in advance of use. The subject or the subject’s legally acceptable
representative should be informed in a timely manner if new information becomes
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available that may be relevant to the subject’s willingness to continue participation
in the trial. The communication of this information should be documented.
4.8.3
Neither the investigator, nor the trial staff, should coerce or unduly influence a subject
to participate or to continue to participate in a trial.
4.8.4
None of the oral and written information concerning the trial, including the written
informed consent form, should contain any language that causes the subject or the
subject’s legally acceptable representative to waive or to appear to waive any legal
rights, or that releases or appears to release the investigator, the institution, the
sponsor, or their agents from liability for negligence.
4.8.5
The investigator, or a person designated by the investigator, should fully inform the
subject or, if the subject is unable to provide informed consent, the subject’s legally
acceptable representative, of all pertinent aspects of the trial including the written
information and the approval/ favorable opinion by the IRB/IEC.
4.8.6
The language used in the oral and written information about the trial, including the
written informed consent form, should be as non-technical as practical and should
be understandable to the subject or the subject's legally acceptable representative
and the impartial witness, where applicable.
4.8.7
Before informed consent may be obtained, the investigator, or a person designated by
the investigator, should provide the subject or the subject’s legally acceptable
representative ample time and opportunity to inquire about details of the trial and to
decide whether or not to participate in the trial. All questions about the trial should
be answered to the satisfaction of the subject or the subject’s legally acceptable
representative.
4.8.8
Prior to a subject’s participation in the trial, the written informed consent form should
be signed and personally dated by the subject or by the subject’s legally acceptable
representative, and by the person who conducted the informed consent discussion.
4.8.9
If a subject is unable to read or if a legally acceptable representative is unable to read,
an impartial witness should be present during the entire informed consent discussion.
After the written informed consent form and any other written information to be
provided to subjects, is read and explained to the subject or the subject's legally
acceptable representative, and after the subject or the subject’s legally acceptable
representative has orally consented to the subject’s participation in the trial and, if
capable of doing so, has signed and personally dated the informed consent form, the
witness should sign and personally date the consent form. By signing the consent form,
the witness attests that the information in the consent form and any other written
information was accurately explained to, and apparently understood by, the subject or
the subject’s legally acceptable representative, and that informed consent was freely
given by the subject or the subject’s legally acceptable representative.
4.8.10 Both the informed consent discussion and the written informed consent form and
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any other written information to be provided to subjects should include explanations
of the following:
(a) That the trial involves research.
(b) The purpose of the trial.
(c) The trial treatment(s) and the probability for random assignment to each treatment.
(d) The trial procedures to be followed, including all invasive procedures.
(e) The subject’s responsibilities.
(f) Those aspects of the trial that are experimental.
(g) The reasonably foreseeable risks or inconveniences to the subject and, when
applicable, to an embryo, fetus, or nursing infant.
(h) The reasonably expected benefits. When there is no intended clinical benefit to
the subject, the subject should be made aware of this.
(i) The alternative procedure(s) or course(s) of treatment that may be available to
the subject, and their important potential benefits and risks.
(j) The compensation and/or treatment available to the subject in the event of trial-
related injury.
(k) The anticipated prorated payment, if any, to the subject for participating in the trial.
(l) The anticipated expenses, if any, to the subject for participating in the trial.
(m) That the subject’s participation in the trial is voluntary and that the subject may
refuse to participate or withdraw from the trial, at any time, without penalty or
loss of benefits to which the subject is otherwise entitled.
(n) That the monitor(s), the auditor(s), the IRB/IEC, and the regulatory
authority(ies) will be granted direct access to the subject’s original medical records
for verification of clinical trial procedures and/or data, without violating the
confidentiality of the subject, to the extent permitted by the applicable laws and
regulations and that, by signing a written informed consent form, the subject or
the subject’s legally acceptable representative is authorizing such access.
(o) That records identifying the subject will be kept confidential and, to the extent
permitted by the applicable laws and/or regulations, will not be made publicly
available. If the results of the trial are published, the subject’s identity will
remain confidential.
(p) That the subject or the subject’s legally acceptable representative will be informed
in a timely manner if information becomes available that may be relevant to the
subject’s willingness to continue participation in the trial.
(q) The person(s) to contact for further information regarding the trial and the rights
of trial subjects, and whom to contact in the event of trial-related injury.
(r) The foreseeable circumstances and/or reasons under which the subject’s
participation in the trial may be terminated.
(s) The expected duration of the subject’s participation in the trial.
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(t) The approximate number of subjects involved in the trial.
4.8.11 Prior to participation in the trial, the subject or the subject's legally acceptable
representative should receive a copy of the signed and dated written informed
consent form and any other written information provided to the subjects. During a
subject’s participation in the trial, the subject or the subject’s legally acceptable
representative should receive a copy of the signed and dated consent form updates
and a copy of any amendments to the written information provided to subjects.
4.8.12 When a clinical trial (therapeutic or non-therapeutic) includes subjects who can only
be enrolled in the trial with the consent of the subject’s legally acceptable
representative (e.g., minors, or patients with severe dementia), the subject should be
informed about the trial to the extent compatible with the subject’s understanding and,
if capable, the subject should sign and personally date the written informed consent.
4.8.13 Except as described in 4.8.14, a non-therapeutic trial (i.e., a trial in which there is
no anticipated direct clinical benefit to the subject), should be conducted in subjects
who personally give consent and who sign and date the written informed consent form.
4.8.14 Nontherapeutic trials may be conducted in subjects with consent of a legally
acceptable representative provided the following conditions are fulfilled:
(a) The objectives of the trial cannot be met by means of a trial in subjects who can
give informed consent personally.
(b) The foreseeable risks to the subjects are low.
(c) The negative impact on the subject’s well-being is minimized and low.
(d) The trial is not prohibited by law.
(e) The approval/favorable opinion of the IRB/IEC is expressly sought on the inclusion
of such subjects, and the written approval/ favorable opinion covers this aspect.
Such trials, unless an exception is justified, should be conducted in patients having
a disease or condition for which the investigational product is intended. Subjects in
these trials should be particularly closely monitored and should be withdrawn if they
appear to be unduly distressed.
4.8.15 In emergency situations, when prior consent of the subject is not possible, the consent
of the subject’s legally acceptable representative, if present, should be requested.
When prior consent of the subject is not possible, and the subject’s legally
acceptable representative is not available, enrollment of the subject should require
measures described in the protocol and/or elsewhere, with documented
approval/favorable opinion by the IRB/IEC, to protect the rights, safety and well-being
of the subject and to ensure compliance with applicable regulatory requirements. The
subject or the subject’s legally acceptable representative should be informed about
the trial as soon as possible and consent to continue and other consent as appropriate
(see s e c t i o n 4.8.10) should be requested.
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4.9
Records and Reports
ADDENDUM
4.9.0 The investigator/institution should maintain adequate and accurate source documents
and trial records that include all pertinent observations on each of the site's trial
subjects. Source data should be attributable, legible, contemporaneous, original,
accurate, and complete. Changes to source data should be traceable, should not
obscure the original entry, and should be explained if necessary (e.g., via an audit
trail).
4.9.1
The investigator should ensure the accuracy, completeness, legibility, and timeliness
of the data reported to the sponsor in the CRFs and in all required reports.
4.9.2
Data reported on the CRF, that are derived from source documents, should be
consistent with the source documents or the discrepancies should be explained.
4.9.3
Any change or correction to a CRF should be dated, initialed, and explained (if
necessary) and should not obscure the original entry (i.e., an audit trail should be
maintained); this applies to both written and electronic changes or corrections (see
5.18.4(n)). Sponsors should provide guidance to investigators and/or the investigators'
designated representatives on making such corrections. Sponsors should have written
procedures to assure that changes or corrections in CRFs made by sponsor's
designated representatives are documented, are necessary, and are endorsed by the
investigator. The investigator should retain records of the changes and corrections.
4.9.4
The investigator/institution should maintain the trial documents as specified in
Essential Documents for the Conduct of a Clinical Trial (see section 8.) and as
required by the applicable regulatory requirement(s). The investigator/institution
should take measures to prevent accidental or premature destruction of these
documents.
4.9.5
Essential documents should be retained until at least 2-years after the last approval of
a marketing application in an ICH region and until there are no pending or
contemplated marketing applications in an ICH region or at least 2 years have elapsed
since the formal discontinuation of clinical development of the investigational
product. These documents should be retained for a longer period, however, if
required by the applicable regulatory requirements or by an agreement with the
sponsor. It is the responsibility of the sponsor to inform the investigator/institution as
to when these documents no longer need to be retained (see section 5.5.12).
4.9.6
The financial aspects of the trial should be documented in an agreement between
the sponsor and the investigator/institution.
4.9.7
Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, the
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related records.
4.10
Progress Reports
4.10.1 The investigator should submit written summaries of the trial’s status to the IRB/IEC
annually, or more frequently, if requested by the IRB/IEC.
4.10.2 The investigator should promptly provide written reports to the sponsor, the IRB/IEC
(see section 3.3.8) and, where applicable, the institution on any changes significantly
affecting the conduct of the trial, and/or increasing the risk to subjects.
4.11
Safety Reporting
4.11.1 All SAEs should be reported immediately to the sponsor except for those SAEs that
the protocol or other document (e.g., Investigator's Brochure) identifies as not needing
immediate reporting. The immediate reports should be followed promptly by detailed,
written reports. The immediate and follow-up reports should identify subjects by
unique code numbers assigned to the trial subjects rather than by the subjects' names,
personal identification numbers, and/or addresses. The investigator should also
comply with the applicable regulatory requirement(s) related to the reporting of
unexpected serious adverse drug reactions to the regulatory authority(ies) and the
IRB/IEC.
4.11.2 Adverse events and/or laboratory abnormalities identified in the protocol as critical
to safety evaluations should be reported to the sponsor according to the reporting
requirements and within the time periods specified by the sponsor in the protocol.
4.11.3 For reported deaths, the investigator should supply the sponsor and the IRB/IEC with
any additional requested information (e.g., autopsy reports and terminal medical
reports).
4.12
Premature Termination or Suspension of a Trial
If the trial is prematurely terminated or suspended for any reason, the
investigator/institution should promptly inform the trial subjects, should assure appropriate
therapy and follow-up for the subjects, and, where required by the applicable regulatory
requirement(s), should inform the regulatory authority(ies). In addition:
4.12.1 If the investigator terminates or suspends a trial without prior agreement of the
sponsor, the investigator should inform the institution, where applicable, and the
investigator/institution should promptly inform the sponsor and the IRB/IEC, and
should provide the sponsor and the IRB/IEC a detailed written explanation of the
termination or suspension.
4.12.2 If the sponsor terminates or suspends a trial (see section 5.21), the investigator should
promptly inform the institution where applicable and the investigator/institution should
promptly inform the IRB/IEC, and provide the IRB/IEC a detailed written explanation of
the termination or suspension.
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4.12.3 If the IRB/IEC terminates or suspends its approval/favorable opinion of a trial (see
sections 3.1.2 and 3.3.9), the investigator should inform the institution where
applicable and the investigator/institution should promptly notify the sponsor and
provide the sponsor with a detailed written explanation of the termination or
suspension.
4.13 Final Report(s) by Investigator
Upon completion of the trial, the investigator, where applicable, should inform the
institution; the investigator/institution should provide the IRB/IEC with a summary of the
trial's outcome, and the regulatory authority(ies) with any reports required.
5.
SPONSOR
ADDENDUM
5.0
Quality Management
The sponsor should implement a system to manage quality throughout all stages of the
trial process.
Sponsors should focus on trial activities essential to ensuring human subject protection and
the reliability of trial results. Quality management includes the design of efficient clinical trial
protocols, tools, and procedures for data collection and processing, as well as the collection of
information that is essential to decision making.
The methods used to assure and control the quality of the trial should be proportionate to
the risks inherent in the trial and the importance of the information collected. The sponsor
should ensure that all aspects of the trial are operationally feasible and should avoid
unnecessary complexity, procedures, and data collection. Protocols, case report forms, and
other operational documents should be clear, concise, and consistent.
The quality management system should use a risk-based approach as described below.
5.0.1
Critical Process and Data Identification
During protocol development, the sponsor should identify those processes and data
that are critical to ensure human subject protection and the reliability of trial results.
5.0.2
Risk Identification
The sponsor should identify risks to critical trial processes and data. Risks should be
considered at both the system level (e.g., standard operating procedures,
computerized systems, a n d personnel) and clinical trial level (e.g., trial design, data
collection, a n d informed consent process).
5.0.3
Risk Evaluation
The sponsor should evaluate the identified risks, against existing risk controls by
considering:
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(a)
(b)
(c)
5.0.4
The likelihood of errors occurring.
The extent to which such errors would be detectable.
The impact of such errors on human subject protection and reliability of trial
results.
Risk Control
The sponsor should decide which risks to reduce and/or which risks to accept.
The approach used to reduce risk to an acceptable level should be proportionate to the
significance of the risk. Risk reduction activities may be incorporated in protocol
design and implementation, monitoring plans, agreements between parties defining
roles and responsibilities, systematic safeguards to ensure adherence to standard
operating procedures, and training in processes and procedures.
Predefined quality tolerance limits should be established, taking into consideration
the medical and statistical characteristics of the variables as well as the statistical
design of the trial, to identify systematic issues that can impact subject safety or
reliability of trial results. Detection of deviations from the predefined quality tolerance
limits should trigger an evaluation to determine if action is needed.
5.0.5
Risk Communication
The sponsor should document quality management activities. The sponsor should
communicate quality management activities to those who are involved in or affected
by such activities, to facilitate risk review and continual improvement during clinical
trial execution.
5.0.6
Risk Review
The sponsor should periodically review risk control measures to ascertain whether
the implemented quality management activities remain effective and relevant, taking
into account emerging knowledge and experience.
5.0.7
Risk Reporting
The sponsor should describe the quality management approach implemented in the
trial and summarize important deviations from the predefined quality tolerance
limits and remedial actions taken in the clinical study report (ICH E3, section 9.6
Data Quality Assurance).
5.l
Quality Assurance and Quality Control
5.1.1
The sponsor is responsible for implementing and maintaining quality assurance
and quality control systems with written SOPs to ensure that trials are conducted and
data are generated, documented (recorded), and reported in compliance with the
protocol, GCP, and the applicable regulatory requirement(s).
5.1.2
The sponsor is responsible for securing agreement from all involved parties to ensure
direct access (see section 1.21) to all trial-related sites, source data/documents, and reports
for the purpose of monitoring and auditing by the sponsor, and inspection by domestic and
foreign regulatory authorities.
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5.1.3
Quality control should be applied to each stage of data handling to ensure that all data
are reliable and have been processed correctly.
5.1.4
Agreements, made by the sponsor with the investigator/institution and any other
parties involved with the clinical trial, should be in writing, as part of the protocol
or in a separate agreement.
5.2
Contract Research Organization (CRO)
5.2.1
A sponsor may transfer any or all of the sponsor's trial-related duties and functions to
a CRO, but the ultimate responsibility for the quality and integrity of the trial data
always resides with the sponsor. The CRO should implement quality assurance and
quality control.
5.2.2
Any trial-related duty and function that is transferred to and assumed by a CRO should
be specified in writing.
ADDENDUM
The sponsor should ensure oversight of any trial-related duties and functions carried
out on its behalf, including trial-related duties and functions that are subcontracted to
another party by the sponsor's contracted CRO(s).
5.2.3
Any trial-related duties and functions not specifically transferred to and assumed by
a CRO are retained by the sponsor.
5.2.4
All references to a sponsor in this guidance also apply to a CRO to the extent that a
CRO has assumed the trial-related duties and functions of a sponsor.
5.3
Medical Expertise
The sponsor should designate appropriately qualified medical personnel who will be readily
available to advise on trial- related medical questions or problems. If necessary, outside
consultant(s) may be appointed for this purpose.
5.4
Trial Design
5.4.1
The sponsor should utilize qualified individuals (e.g., biostatisticians, clinical
pharmacologists, and physicians) as appropriate, throughout all stages of the trial
process, from designing the protocol and CRFs and planning the analyses to
analyzing and preparing interim and final clinical trial reports.
5.4.2
For further guidance: Clinical Trial Protocol and Protocol Amendment(s) (see section
6), the ICH Guideline for Structure and Content of Clinical Study Reports, and other
appropriate ICH guidance on trial design, protocol, and conduct.
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5.5
Trial Management, Data Handling, and Recordkeeping
5.5.1
The sponsor should utilize appropriately qualified individuals to supervise the overall
conduct of the trial, to handle the data, to verify the data, to conduct the statistical
analyses, and to prepare the trial reports.
5.5.2
The sponsor may consider establishing an independent data monitoring committee
(IDMC) to assess the progress of a clinical trial, including the safety data and the
critical efficacy endpoints at intervals, and to recommend to the sponsor whether
to continue, modify, or stop a trial. The IDMC should have written operating
procedures and maintain written records of all its meetings.
5.5.3
When using electronic trial data handling and/or remote electronic trial data systems,
the sponsor should:
(a) Ensure and document that the electronic data processing system(s) conforms to
the sponsor's established requirements for completeness, accuracy, reliability, and
consistent intended performance (i.e., validation).
ADDENDUM
The sponsor should base their approach to validation of such systems on a risk
assessment that takes into consideration the intended use of the system and the
potential of the system to affect human subject protection and reliability of trial
results.
(b) Maintains SOPs for using these systems.
ADDENDUM
The SOPs should cover system setup, installation, and use. The SOPs should
describe system validation and functionality testing, data collection and handling,
system maintenance, system security measures, change control, data backup,
recovery, contingency planning, and decommissioning. The responsibilities of the
sponsor, investigator, and other parties with respect to the use of these
computerized systems should be clear, and the users should be provided with
training in their use.
(c) Ensure that the systems are designed to permit data changes in such a way that
the data changes are documented and that there is no deletion of entered data (i.e.,
maintain an audit trail, data trail, edit trail).
(d) Maintain a security system that prevents unauthorized access to the data.
(e) Maintain a list of the individuals who are authorized to make data changes (see
sections 4.1.5 and 4.9.3).
(f) Maintain adequate backup of the data.
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(g) Safeguard the blinding, if any (e.g., maintain the blinding during data entry and
processing).
ADDENDUM
(h) Ensure the integrity of the data, including any data that describe the context,
content, and structure. This is particularly important when making changes to the
computerized systems, such as software upgrades or migration of data.
5.5.4
If data are transformed during processing, it should always be possible to compare
the original data and observations with the processed data.
5.5.5
The sponsor should use an unambiguous subject identification code (see 1.58) that
allows identification of all the data reported for each subject.
5.5.6
The sponsor, or other owners of the data, should retain all of the sponsor-specific
essential documents pertaining to the trial (see section 8. Essential Documents for the
Conduct of a Clinical Trial).
5.5.7
The sponsor should retain all sponsor-specific essential documents in conformance
with the applicable regulatory requirement(s) of the country(ies) where the product
is approved, and/or where the sponsor intends to apply for approval(s).
5.5.8
If the sponsor discontinues the clinical development of an investigational product
(i.e., for any or all indications, routes of administration, or dosage forms), the
sponsor should maintain all sponsor-specific essential documents for at least 2-years
after formal discontinuation or in conformance with the applicable regulatory
requirement(s).
5.5.9
If the sponsor discontinues the clinical development of an investigational product,
the sponsor should notify all the trial investigators/institutions and all the
regulatory authorities.
5.5.10 Any transfer of ownership of the data should be reported to the appropriate
authority(ies), as required by the applicable regulatory requirement(s).
5.5.11 The sponsor specific essential documents should be retained until at least 2 years
after the last approval of a marketing application in an ICH region and until
there are no pending or contemplated marketing applications in an ICH region or at
least 2 years have elapsed since the formal discontinuation of clinical development
of the investigational product. These documents should be retained for a longer
period, however, if required by the applicable regulatory requirement(s) or if needed
by the sponsor.
5.5.12 The sponsor should inform the investigator(s)/institution(s) in writing of the need
for record retention and should notify the investigator(s)/institution(s) in writing
when the trial-related records are no longer needed.
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5.6
Investigator Selection
5.6.1
The sponsor is responsible for selecting the investigator(s)/institution(s). Each
investigator should be qualified by training and experience and should have
adequate resources (see sections 4.1, 4.2) to properly conduct the trial for which the
investigator is selected. If organization of a coordinating committee and/or selection
of coordinating investigator(s) are to be utilized in multicenter trials, their
organization and/or selection are the sponsor's responsibility.
5.6.2
Before entering an agreement with an investigator/institution to conduct a trial, the
sponsor should provide the investigator(s)/institution(s) with the protocol and an upto- date Investigator's Brochure, and should provide sufficient time for the
investigator/institution to review the protocol and the information provided.
5.6.3
The sponsor should obtain the investigator's/institution's agreement:
(a) To conduct the trial in compliance with GCP, with the applicable regulatory
requirement(s) (see section 4.1.3), and with the protocol agreed to by the sponsor
and given approval/favorable opinion by the IRB/IEC (see section 4.5.1);
(b) To comply with procedures for data recording/reporting;
(c) To permit monitoring, auditing, and inspection (see section 4.1.4); and
(d) To retain the trial- related essential documents until the sponsor informs the
investigator/institution these documents are no longer needed (see sections 4.9.4
and 5.5.12).
The sponsor and the investigator/institution should sign the protocol, or an
alternative document, to confirm this agreement.
5.7
Allocation of Responsibilities
Prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related
duties and functions.
5.8
Compensation to Subjects and Investigators
5.8.1
If required by the applicable regulatory requirement(s), the sponsor should provide
insurance or should indemnify (legal and financial coverage) the investigator/the
institution against claims arising from the trial, except for claims that arise from
malpractice and/or negligence.
5.8.2
The sponsor's policies and procedures should address the costs of treatment of trial
subjects in the event of trial-related injuries in accordance with the applicable
regulatory requirement(s).
5.8.3
When trial subjects receive compensation, the method and manner of compensation
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should comply with applicable regulatory requirement(s).
5.9
Financing
The financial aspects of the trial should be documented in an agreement between the sponsor
and the investigator/institution.
5.10
Notification/Submission to Regulatory Authority(ies)
Before initiating the clinical trial(s), the sponsor (or the sponsor and the investigator, if
required by the applicable regulatory requirement(s)) should submit any required
application(s) to the appropriate authority(ies) for review, acceptance, and/or permission (as
required by the applicable regulatory requirement(s)) to begin the trial(s). Any
notification/submission should be dated and contain sufficient information to identify the
protocol.
5.11
Confirmation of Review by IRB/IEC
5.11.1 The sponsor should obtain from the investigator/institution:
(a) The name and address of the investigator's/institution's IRB/IEC.
(b) A statement obtained from the IRB/IEC that it is organized and operates according
to GCP and the applicable laws and regulations.
(c) Documented IRB/IEC approval/favorable opinion and, if requested by the sponsor,
a current copy of protocol, written informed consent form(s) and any other
written information to be provided to subjects, subject recruiting procedures, and
documents related to payments and compensation available to the subjects, and
any other documents that the IRB/IEC may have requested.
5.11.2
If the IRB/IEC conditions its approval/favorable opinion upon change(s) in any
aspect of the trial, such as modification(s) of the protocol, written informed consent
form and any other written information to be provided to subjects, and/or other
procedures, the sponsor should obtain from the investigator/institution a copy of the
modification(s) made and the date approval/favorable opinion was given by the
IRB/IEC.
5.11.3 The sponsor should obtain from the investigator/institution documentation and dates
of any IRB/IEC reapprovals/reevaluations with favorable opinion, and of any
withdrawals or suspensions of approval/favorable opinion.
5.12
Information on Investigational Product(s)
5.12.1 When planning trials, the sponsor should ensure that sufficient safety and efficacy
data from nonclinical studies and/or clinical trials are available to support human
exposure by the route, at the dosages, for the duration, and in the trial population to be
studied.
The sponsor should update the Investigator's Brochure as significant new information
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becomes available (see section 7. Investigator's Brochure).
5.13
Manufacturing, Packaging, Labeling, and Coding Investigational Product(s)
5.13.1 The sponsor should ensure that the investigational product(s) (including active
comparator(s) and placebo, if applicable) is characterized as appropriate to the stage
of development of the product(s), is manufactured in accordance with any applicable
GMP, and is coded and labelled in a manner that protects the blinding, if applicable. In
addition, the labeling should comply with applicable regulatory requirement(s).
5.13.2 The sponsor should determine, for the investigational product(s), acceptable storage
temperatures, storage conditions (e.g., protection from light), storage times,
reconstitution fluids and procedures, and devices for product infusion, if any. The
sponsor should inform all involved parties (e.g., monitors, investigators, pharmacists,
storage managers) of these determinations.
5.13.3 The investigational product(s) should be packaged to prevent contamination and
unacceptable deterioration during transport and storage.
5.13.4 In blinded trials, the coding system for the investigational product(s) should include
a mechanism that permits rapid identification of the product(s) in case of a medical
emergency, but does not permit undetectable breaks of the blinding.
5.13.5 If significant formulation changes are made in the investigational or comparator
product(s) during the course of clinical development, the results of any additional
studies of the formulated product(s) (e.g., stability, dissolution rate, bioavailability)
needed to assess whether these changes would significantly alter the pharmacokinetic
profile of the product should be available prior to the use of the new formulation in
clinical trials.
5.14
Supplying and Handling Investigational Product(s)
5.14.1 The sponsor is responsible for supplying the investigator(s)/institution(s) with the
investigational product(s).
5.14.2 The sponsor should not supply an investigator/institution with the investigational
product(s) until the sponsor obtains all required documentation (e.g.,
approval/favorable opinion from IRB/IEC and regulatory authority(ies)).
5.14.3 The sponsor should ensure that written procedures include instructions that the
investigator/institution should follow for the handling and storage of investigational
product(s) for the trial and documentation thereof. The procedures should address
adequate and safe receipt, handling, storage, dispensing, retrieval of unused product
from subjects, and return of unused investigational product(s) to the sponsor (or
alternative disposition if authorized by the sponsor and in compliance with the
applicable regulatory requirement(s)).
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5.14.4 The sponsor should:
(a)
Ensure timely delivery of investigational product(s) to the investigator(s).
(b)
Maintain records that document shipment, receipt, disposition, return, and
destruction of the investigational product(s) (see section 8. Essential Documents
for the Conduct of a Clinical Trial).
Maintain a system for retrieving investigational products and documenting this
retrieval (e.g., for deficient product recall, reclaim after trial completion, expired
product reclaim).
(c)
(d)
Maintain a system for the disposition of unused investigational product(s) and for
the documentation of this disposition.
5.14.5 The sponsor should:
(a) Take steps to ensure that the investigational product(s) are stable over the period
of use.
(b) Maintain sufficient quantities of the investigational product(s) used in the trials
to reconfirm specifications, should this become necessary, and maintain records of
batch sample analyses and characteristics. To the extent stability permits,
samples should be retained either until the analyses of the trial data are complete or
as required by the applicable regulatory requirement(s), whichever represents the
longer retention period.
5.15
Record Access
5.15.1 The sponsor should ensure that it is specified in the protocol or other written
agreement that the investigator(s)/institution(s) provide direct access to source
data/documents for trial-related monitoring, audits, IRB/IEC review, and regulatory
inspection.
5.15.2 The sponsor should verify that each subject has consented, in writing, to direct access
to his/her original medical records for trial-related monitoring, audit, IRB/IEC review,
and regulatory inspection.
5.16
Safety Information
5.16.1 The sponsor is responsible for the ongoing safety evaluation of the investigational
product(s).
5.16.2 The sponsor should promptly notify all concerned investigator(s)/institution(s) and
the regulatory authority(ies) of findings that could affect adversely the safety of
subjects, impact the conduct of the trial, or alter the IRB/IEC's approval/favorable
opinion to continue the trial.
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5.17
Adverse Drug Reaction Reporting
5.17.1 The sponsor should expedite the reporting to all concerned
investigator(s)/institutions(s), to the IRB(s)/IEC(s), where required, and to the
regulatory authority(ies) of all adverse drug reactions (ADRs) that are both serious and
unexpected.
5.17.2 Such expedited reports should comply with the applicable regulatory requirement(s)
and with the ICH Guideline for Clinical Safety Data Management: Definitions and
Standards for Expedited Reporting.
5.17.3 The sponsor should submit to the regulatory authority(ies) all safety updates and
periodic reports, as required by applicable regulatory requirement(s).
5.18
Monitoring
5.18.1 Purpose
The purposes of trial monitoring are to verify that:
(a) The rights and well-being of human subjects are protected.
(b) The reported trial data are accurate, complete, and verifiable from source documents.
(c) The conduct of the trial is in compliance with the currently approved
protocol/amendment(s), with GCP, and with the applicable regulatory
requirement(s).
5.18.2 Selection and Qualifications of Monitors
(a) Monitors should be appointed by the sponsor.
(b) Monitors should be appropriately trained, and should have the scientific and/or
clinical knowledge needed to monitor the trial adequately. A monitor's
qualifications should be documented.
(c) Monitors should be thoroughly familiar with the investigational product(s), the
protocol, written informed consent form and any other written information to be
provided to subjects, the sponsor's SOPs, GCP, and the applicable regulatory
requirement(s).
5.18.3 Extent and Nature of Monitoring
The sponsor should ensure that the trials are adequately monitored. The sponsor should
determine the appropriate extent and nature of monitoring. The determination of the
extent and nature of monitoring should be based on considerations such as the objective,
purpose, design, complexity, blinding, size, and endpoints of the trial. In general there is a
need for on-site monitoring, before, during, and after the trial; however, in exceptional
circumstances the sponsor may determine that central monitoring in conjunction with
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procedures such as investigators' training and meetings, and extensive written guidance
can assure appropriate conduct of the trial in accordance with GCP. Statistically
controlled sampling may be an acceptable method for selecting the data to be verified.
ADDENDUM
The sponsor should develop a systematic, prioritized, risk-based approach to
monitoring clinical trials. The flexibility in the extent and nature of monitoring
described in this section is intended to permit varied approaches that improve the
effectiveness and efficiency of monitoring. The sponsor may choose on-site
monitoring, a combination of on-site and centralized monitoring, or, where justified,
centralized monitoring. The sponsor should document the rationale for the chosen
monitoring strategy (e.g., in the monitoring plan).
On-site monitoring is performed at the sites at which the clinical trial is being
conducted. Centralized monitoring is a remote evaluation of accumulating data,
performed in a timely manner, supported by appropriately qualified and trained
persons (e.g., data managers, biostatisticians).
Centralized monitoring processes provide additional monitoring capabilities that can
complement and reduce the extent and/or frequency of on-site monitoring and help
distinguish between reliable data and potentially unreliable data.
Review that may include statistical analyses of accumulating data from centralized
monitoring can be used to:
(a) Identify missing data, inconsistent data, data outliers, unexpected lack of
variability and protocol deviations
(b) Examine data trends such as the range, consistency, and variability of data within
and across sites
(c) Evaluate for systematic or significant errors in data collection and reporting at a
site or across sites; or potential data manipulation or data integrity problems
(d) Analyze site characteristics and performance metrics
(e) Select sites and/or processes for targeted on-site monitoring.
5.18.4 Monitor's Responsibilities
The monitor(s), in accordance with the sponsor's requirements, should ensure that the
tri al is conducted and documented properly by carrying out the following activities
when relevant and necessary to the trial and the trial site:
(a) Acting as the main line of communication between the sponsor and the investigator.
(b) Verifying that the investigator has adequate qualifications and resources (see
sections 4.1, 4.2, 5.6) and these remain adequate throughout the trial period, that
facilities including laboratories and equipment, and staff, are adequate to safely and
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properly conduct the trial and remain adequate throughout the trial period.
(c) Verifying, for the investigational product(s):
(i) That storage times and conditions are acceptable, and that supplies are
sufficient throughout the trial.
(ii) That the investigational product(s) are supplied only to subjects who are
eligible to receive it and at the protocol specified dose(s).
(iii) That subjects are provided with necessary instruction on properly using,
handling, storing, and returning the investigational product(s).
(iv) That the receipt, use, and return of the investigational product(s) at the
trial sites are controlled and documented adequately.
(v) That the disposition of unused investigational product(s) at the trial sites
complies with applicable regulatory requirement(s) and is in accordance
with the sponsor.
(d) Verifying that the investigator follows the approved protocol and all approved
amendment(s), if any.
(e) Verifying that written informed consent was obtained before each subject's
participation in the trial.
(f) Ensuring that the investigator receives the current Investigator's Brochure, all
documents, and all trial supplies needed to conduct the trial properly and to
comply with the applicable regulatory requirement(s).
(g) Ensuring that the investigator and the investigator's trial staff are adequately
informed about the trial.
(h) Verifying that the investigator and the investigator's trial staff are performing
the specified trial functions, in accordance with the protocol and any other written
agreement between the sponsor and the investigator/institution, and have not
delegated these functions to unauthorized individuals.
(i) Verifying that the investigator is enrolling only eligible subjects.
(j) Reporting the subject recruitment rate.
(k) Verifying that source documents and other trial records are accurate, complete,
kept up-to-date, and maintained.
(l) Verifying that the investigator provides all the required reports, notifications,
applications, and submissions, and that these documents are accurate, complete,
timely, legible, dated, and identify the trial.
(m) Checking the accuracy and completeness of the CRF entries, source documents
and other trial-related records against each other. The monitor specifically should
verify that:
(i) The data required by the protocol are reported accurately on the CRFs and
are consistent with the source documents.
(ii) Any dose and/or therapy modifications are well documented for each of
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the trial subjects.
(iii) Adverse events, concomitant medications and intercurrent illnesses are
reported in accordance with the protocol on the CRFs.
(iv) Visits that the subjects fail to make, tests that are not conducted, and
examinations that are not performed are clearly reported as such on the
CRFs.
(v) All withdrawals and dropouts of enrolled subjects from the trial are
reported and explained on the CRFs.
(n) Informing the investigator of any CRF entry error, omission, or illegibility. The
monitor should ensure that appropriate corrections, additions, or deletions are
made, dated, explained (if necessary), and initialed by the investigator or by a
member of the investigator's trial staff who is authorized to initial CRF changes
for the investigator. This authorization should be documented.
(o) Determining whether all adverse events (AEs) are appropriately reported within
the time periods required by GCP, the protocol, the IRB/IEC, the sponsor, and the
applicable regulatory requirement(s).
(p) Determining whether the investigator is maintaining the essential documents (see
section 8. Essential Documents for the Conduct of a Clinical Trial).
(q) Communicating deviations from the protocol, SOPs, GCP, and the applicable
regulatory requirements to the investigator and taking appropriate action designed
to prevent recurrence of the detected deviations.
5.18.5 Monitoring Procedures
The monitor(s) should follow the sponsor's established written SOPs as well as those
procedures that are specified by the sponsor for monitoring a specific trial.
5.18.6 Monitoring Report
(a) The monitor should submit a written report to the sponsor after each trial-site visit
or trial-related communication.
(b) Reports should include the date, site, name of the monitor, and name of the
investigator or other individual(s) contacted.
(c) Reports should include a summary of what the monitor reviewed and the
monitor's statements concerning the significant findings/facts, deviations and
deficiencies, conclusions, actions taken or to be taken and/or actions recommended
to secure compliance.
(d) The review and follow-up of the monitoring report with the sponsor should be
documented by the sponsor's designated representative.
ADDENDUM
(e) Reports of on-site and/or centralized monitoring should be provided to the
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sponsor (including appropriate management and staff responsible for trial and site
oversight) in a timely manner for review and follow up. Results of monitoring
activities should be documented in sufficient detail to allow verification of
compliance with the monitoring plan. Reporting of centralized monitoring
activities should be regular and may be independent from site visits.
ADDENDUM
5.18.7 Monitoring Plan
The sponsor should develop a monitoring plan that is tailored to the specific human
subject protection and data integrity risks of the trial. The plan should describe the
monitoring strategy, the monitoring responsibilities of all the parties involved, the various
monitoring methods to be used, and the rationale for their use. The plan should also
emphasize the monitoring of critical data and processes. Particular attention should be
given to those aspects that are not routine clinical practice and that require additional
training. The monitoring plan should reference the applicable policies and procedures.
5.19
Audit
If or when sponsors perform audits, as part of implementing quality assurance, they should
consider:
5.19.1 Purpose
The purpose of a sponsor's audit, which is independent of and separate from routine
monitoring or quality control functions, should be to evaluate trial conduct and
compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements.
5.19.2 Selection and Qualification of Auditors
(a) The sponsor should appoint individuals, who are independent of the clinical
trials/systems, to conduct audits.
(b) The sponsor should ensure that the auditors are qualified by training and
experience to conduct audits properly. An auditor's qualifications should be
documented.
5.19.3 Auditing Procedures
(a) The sponsor should ensure that the auditing of clinical trials/systems is conducted
in accordance with the sponsor's written procedures on what to audit, how to
audit, the frequency of audits, and the form and content of audit reports.
(b) The sponsor's audit plan and procedures for a trial audit should be guided by
the importance of the trial to submissions to regulatory authorities, the number of
subjects in the trial, the type and complexity of the trial, the level of risks to the
trial subjects, and any identified problem(s).
(c) The observations and findings of the auditor(s) should be documented.
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(d) To preserve the independence and value of the audit function, the regulatory
authority(ies) should not routinely request the audit reports. Regulatory
authority(ies) may seek access to an audit report on a case-by-case basis when
evidence of serious GCP non-compliance exists, or in the course of legal
proceedings.
(e) When required by applicable law or regulation, the sponsor should provide an
audit certificate.
5.20
Noncompliance
5.20.1 Noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory
requirement(s) by an investigator/institution, or by member(s) of the sponsor's staff
should lead to prompt action by the sponsor to secure compliance.
ADDENDUM
If noncompliance that significantly affects or has the potential to significantly affect
human subject protection or reliability of trial results is discovered, the sponsor
should perform a root cause analysis and implement appropriate corrective and
preventive actions.
5.20.2 If the monitoring and/or auditing identifies serious and/or persistent noncompliance on
the part of an investigator/institution, the sponsor should terminate the
investigator's/institution's participation in the trial. When an investigator's/institution's
participation is terminated because of noncompliance, the sponsor should notify
promptly the regulatory authority(ies).
5.21
Premature Termination or Suspension of a Trial
If a trial is prematurely terminated or suspended, the sponsor should promptly inform the
investigators/institutions, and the regulatory authority(ies) of the termination or suspension
and the reason(s) for the termination or suspension. The IRB/IEC should also be informed
promptly and provided the reason(s) for the termination or suspension by the sponsor or
by the investigator/institution, as specified by the applicable regulatory requirement(s).
5.22 Clinical Trial/Study Reports
Whether the trial is completed or prematurely terminated, the sponsor should ensure that
the clinical trial reports are prepared and provided to the regulatory agency(ies) as required
by the applicable regulatory requirement(s). The sponsor should also ensure that the clinical
trial reports in marketing applications meet the standards of the ICH Guidance for Structure
and Content of Clinical Study Reports. (NOTE: The ICH Guidance for Structure and Content
of Clinical Study Reports specifies that abbreviated study reports may be acceptable in certain
cases.)
5.23
Multicenter Trials
For multicenter trials, the sponsor should ensure that:
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5.23.1 All investigators conduct the trial in strict compliance with the protocol agreed to by
the sponsor and, if required, by the regulatory authority(ies), and given
approval/favorable opinion by the IRB/IEC.
5.23.2 The CRFs are designed to capture the required data at all multicenter trial sites. For
those investigators who are collecting additional data, supplemental CRFs should also
be provided that are designed to capture the additional data.
5.23.3 The responsibilities of coordinating investigator(s) and the other participating
investigators are documented prior to the start of the trial.
5.23.4 All investigators are given instructions on following the protocol, on complying with
a uniform set of standards for the assessment of clinical and laboratory findings,
and on completing the CRFs.
5.23.5 Communication between investigators is facilitated.
6.
CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S)
The contents of a trial protocol should generally include the following topics. However,
site specific information may be provided on separate protocol page(s), or addressed in a
separate agreement, and some of the information listed below may be contained in other
protocol referenced documents, such as an Investigator's Brochure.
6.l
General Information
6.1.1
Protocol title, protocol identifying number, and date. Any amendment(s) should also
bear the amendment number(s) and date(s).
6.1.2
Name and address of the sponsor and monitor (if other than the sponsor).
6.1.3
Name and title of the person(s) authorized to sign the protocol and the protocol
amendment(s) for the sponsor.
6.1.4
Name, title, address, and telephone number(s) of the sponsor's medical expert (or
dentist when appropriate) for the trial.
6.1.5
Name and title of the investigator(s) who is (are) responsible for conducting the trial,
and the address and telephone number(s) of the trial site(s).
6.1.6
Name, title, address, and telephone number(s) of the qualified physician (or dentist,
if applicable), who is responsible for all trial-site related medical (or dental)
decisions (if other than investigator).
6.1.7
Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or
technical department(s) and/or institutions involved in the trial.
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Contains Nonbinding Recommendations
6.2
Background Information
6.2.1
Name and description of the investigational product(s).
6.2.2
A summary of findings from nonclinical studies that potentially have clinical
significance and from clinical trials that are relevant to the trial.
6.2.3
Summary of the known and potential risks and benefits, if any, to human subjects.
6.2.4
Description of and justification for the route of administration, dosage, dosage
regimen, and treatment period(s).
6.2.5
A statement that the trial will be conducted in compliance with the protocol, GCP, and
the applicable regulatory requirement(s).
6.2.6
Description of the population to be studied.
6.2.7
References to literature and data that are relevant to the trial and that provide background
for the trial.
6.3
Trial Objectives and Purpose
A detailed description of the objectives and the purpose of the trial.
6.4
Trial Design
The scientific integrity of the trial and the credibility of the data from the trial depend
substantially on the trial design. A description of the trial design should include:
6.4.1
A specific statement of the primary endpoints and the secondary endpoints, if any, to
be measured during the trial.
6.4.2
A description of the type/design of trial to be conducted (e.g., double-blind,
placebo-controlled, parallel design) and a schematic diagram of trial design, procedures,
and stages.
6.4.3
A description of the measures taken to minimize/avoid bias, including:
(a) Randomization
(b) Blinding.
6.4.4
A description of the trial treatment(s) and the dosage and dosage regimen of the
investigational product(s). Also include a description of the dosage form, packaging,
and labelling of the investigational product(s).
6.4.5
The expected duration of subject participation, and a description of the sequence
and duration of all trial periods, including follow-up, if any.
6.4.6
A description of the "stopping rules" or "discontinuation criteria" for individual
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subjects, parts of trial, and entire trial.
6.4.7
Accountability procedures for the investigational product(s), including the placebo(s)
and comparator(s), if any.
6.4.8
Maintenance of trial treatment randomization codes and procedures for breaking codes.
6.4.9
The identification of any data to be recorded directly on the CRFs (i.e., no prior
written or electronic record of data), and to be considered to be source data.
6.5
Selection and Withdrawal of Subjects
6.5.1
Subject inclusion criteria.
6.5.2
Subject exclusion criteria.
6.5.3
Subject withdrawal criteria (i.e., terminating investigational product treatment/trial
treatment) and procedures specifying:
(a) When and how to withdraw subjects from the trial/investigational product treatment
(b) The type and timing of the data to be collected for withdrawn subjects
(c) Whether and how subjects are to be replaced
(d) The follow-up for subjects withdrawn from investigational product treatment/trial
treatment.
6.6
Treatment of Subjects
6.6.1
The treatment(s) to be administered, including the name(s) of all the product(s), the
dose(s), the dosing schedule(s), the route/mode(s) of administration, and the
treatment period(s), including the follow-up period(s) for subjects for each
investigational product treatment/trial treatment group/arm of the trial.
6.6.2
Medication(s)/treatment(s) permitted (including rescue medication) and not permitted
before and/or during the trial.
6.6.3
Procedures for monitoring subject compliance.
6.7
Assessment of Efficacy
6.7.1
Specification of the efficacy parameters.
6.7.2
Methods and timing for assessing, recording, and analyzing efficacy parameters.
6.8
Assessment of Safety
6.8.1
Specification of safety parameters.
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6.8.2
The methods and timing for assessing, recording, and analyzing safety parameters.
6.8.3
Procedures for eliciting reports of and for recording and reporting adverse event
and intercurrent illnesses.
6.8.4
The type and duration of the follow-up of subjects after adverse events.
6.9
Statistics
6.9.1
A description of the statistical methods to be employed, including timing of any
planned interim analysis(ses).
6.9.2
The number of subjects planned to be enrolled. In multicenter trials, the numbers
of enrolled subjects projected for each trial site should be specified. Reason for
choice of sample size, including reflections on (or calculations of) the power of the trial
and clinical justification.
6.9.3
The level of significance to be used.
6.9.4
Criteria for the termination of the trial.
6.9.5
Procedure for accounting for missing, unused, and spurious data.
6.9.6
Procedures for reporting any deviation(s) from the original statistical plan (any
deviation(s) from the original statistical plan should be described and justified in
protocol and/or in the final report, as appropriate).
6.9.7
The selection of subjects to be included in the analyses (e.g., all randomized subjects,
all dosed subjects, all eligible subjects, evaluable subjects).
6.10
Direct Access to Source Data/Documents
The sponsor should ensure that it is specified in the protocol or other written agreement that
the investigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review,
and regulatory inspection(s), providing direct access to source data/documents.
6.11
Quality Control and Quality Assurance
6.12 Ethics
Description of ethical considerations relating to the trial.
6.13
Data Handling and Recordkeeping
6.14
Financing and Insurance
Financing and insurance if not addressed in a separate agreement.
6.1 5 Publication Policy
Publication policy, if not addressed in a separate agreement.
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6.16
Supplements
(NOTE: Since the protocol and the clinical trial/study report are closely related, further relevant
information can be found in the ICH Guidance for Structure and Content of Clinical Study
Reports.)
7.
INVESTIGATOR'S BROCHURE
7.l
Introduction
The Investigator's Brochure (IB) is a compilation of the clinical and nonclinical data on
the investigational product(s) that are relevant to the study of the product(s) in human
subjects. Its purpose is to provide the investigators and others involved in the trial with the
information to facilitate their understanding of the rationale for, and their compliance with,
many key features of the protocol, such as the dose, dose frequency/interval, methods of
administration: and safety monitoring procedures. The IB also provides insight to support the
clinical management of the study subjects during the course of the clinical trial. The
information should be presented in a concise, simple, objective, balanced, and nonpromotional form that enables a clinician, or potential investigator, to understand it and make
his/her own unbiased risk-benefit assessment of the appropriateness of the proposed trial. For
this reason, a medically qualified person should generally participate in the editing of an IB,
but the contents of the IB should be approved by the disciplines that generated the described
data.
This guidance delineates the minimum information that should be included in an IB and
provides suggestions for its layout. It is expected that the type and extent of information
available will vary with the stage of development of the investigational product. If the
investigational product is marketed and its pharmacology is widely understood by medical
practitioners, an extensive IB may not be necessary. Where permitted by regulatory authorities,
a basic product information brochure, package leaflet, or labelling may be an appropriate
alternative, provided that it includes current, comprehensive, and detailed information on all
aspects of the investigational product that might be of importance to the investigator. If a
marketed product is being studied for a new use (i.e., a new indication), an IB specific to
that new use should be prepared. The IB should be reviewed at least annually and revised as
necessary in compliance with a sponsor's written procedures. More frequent revision may
be appropriate depending on the stage of development and the generation of relevant new
information. However, in accordance with GCP, relevant new information may be so important
that it should be communicated to the investigators, and possibly to the Institutional Review
Boards (IRBs)/Independent Ethics Committees (IECs) and/or regulatory authorities before it is
included in a revised IB.
Generally, the sponsor is responsible for ensuring that an up-to-date IB is made available to
the investigator(s) and the investigators are responsible for providing the up-to-date IB to the
responsible IRBs/IECs. In the case of an investigator sponsored trial, the sponsorinvestigator should determine whether a brochure is available from the commercial
manufacturer. If the investigational product is provided by the sponsor-investigator, then he or
she should provide the necessary information to the trial personnel. In cases where preparation
of a formal IB is impractical, the sponsor-investigator should provide, as a substitute, an
43
Contains Nonbinding Recommendations
expanded background information section in the trial protocol that contains the minimum
current information described in this guidance.
7.2
General Considerations
The IB should include:
7.2.1 Title Page
This should provide the sponsor's name, the identity of each investigational product
(i.e., research number, chemical or approved generic name, and trade name(s) where
legally permissible and desired by the sponsor), and the release date. It is also
suggested that an edition number, and a reference to the number and date of the
edition it supersedes, be provided. An example is given in Appendix 1.
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Contains Nonbinding Recommendations
7.2.2
Confidentiality Statement
The sponsor may wish to include a statement instructing the investigator/recipients
to treat the IB as a confidential document for the sole information and use of the
investigator's team and the IRB/IEC.
7.3
Contents of the Investigator's Brochure
The IB should contain the following sections, each with literature references where appropriate:
7.3.1
Table of Contents
An example of the Table of Contents is given in Appendix 2
7.3.2
Summary
A brief summary (preferably not exceeding two pages) should be given, highlighting the
significant physical, chemical, pharmaceutical, pharmacological, toxicological,
pharmacokinetic, metabolic, and clinical information available that is relevant to the
stage of clinical development of the investigational product.
7.3.3
Introduction
A brief introductory statement should be provided that contains the chemical name
(and generic and trade name(s) when approved) of the investigational product(s), all
active ingredients, the investigational product (s) pharmacological class and its
expected position within this class (e.g., advantages), the rationale for performing
research with the investigational product(s), and the anticipated prophylactic,
therapeutic, or diagnostic indication(s). Finally, the introductory statement should
provide the general approach to be followed in evaluating the investigational product.
7.3.4
Physical, Chemical, and Pharmaceutical Properties and Formulation
A description should be provided of the investigational product substance(s)
(including the chemical and/or structural formula(e)), and a brief summary should be
given of the relevant physical, chemical, and pharmaceutical properties.
To permit appropriate safety measures to be taken in the course of the trial, a
description of the formulation(s) to be used, including excipients, should be provided
and justified if clinically relevant. Instructions for the storage and handling of the
dosage form(s) should also be given.
Any structural similarities to other known compounds should be mentioned.
7.3.5
Nonclinical Studies
Introduction:
The results of all relevant nonclinical pharmacology, toxicology, pharmacokinetic, and
investigational product metabolism studies should be provided in summary form. This
summary should address the methodology used, the results, and a discussion of the
45
Contains Nonbinding Recommendations
relevance of the findings to the investigated therapeutic and the possible unfavorable
and unintended effects in humans.
The information provided may include the following, as appropriate, if known/available:
•
•
•
•
•
•
•
•
•
Species tested;
Number and sex of animals in each group;
Unit dose (e.g., milligram/kilogram (mg/kg));
Dose interval;
Route of administration;
Duration of dosing;
Information on systemic distribution;
Duration of post-exposure follow-up;
Results, including the following aspects:
− Nature and frequency of pharmacological or toxic effects;
− Severity or intensity of pharmacological or toxic effects;
− Time to onset of effects;
− Reversibility of effects;
− Duration of effects;
− Dose response.
Tabular format/listings should be used whenever possible to enhance the clarity of
the presentation.
The following sections should discuss the most important findings from the studies,
including the dose response of observed effects, the relevance to humans, and any
aspects to be studied in humans. If applicable, the effective and nontoxic dose findings
in the same animal species should be compared (i.e., the therapeutic index should be
discussed). The relevance of this information to the proposed human dosing should
be addressed. Whenever possible, comparisons should be made in terms of blood/tissue
levels rather than on an mg/kg basis.
(a) Nonclinical Pharmacology
A summary of the pharmacological aspects of the investigational product and,
where appropriate, its significant metabolites studied in animals, should be
included. Such a summary should incorporate studies that assess potential
therapeutic activity (e.g., efficacy models, receptor binding, and specificity) as
well as those that assess safety (e.g., special studies to assess pharmacological
actions other than the intended therapeutic effect(s)).
(b) Pharmacokinetics and Product Metabolism in Animals
A summary of the pharmacokinetics and biological transformation and disposition
of the investigational product in all species studied should be given. The discussion
of the findings should address the absorption and the local and systemic
bioavailability of the investigational product and its metabolites, and their
relationship to the pharmacological and toxicological findings in animal species.
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Contains Nonbinding Recommendations
(c) Toxicology
A summary of the toxicological effects found in relevant studies conducted in
different animal species should be described under the following headings where
appropriate:
−
−
−
−
−
−
7.3.6
Single dose
Repeated dose
Carcinogenicity
Special studies (e.g., irritancy and sensitization)
Reproductive toxicity
Genotoxicity (mutagenicity)
Effects in Humans
Introduction
A thorough discussion of the known effects of the investigational product(s) in
humans should be provided, including information on pharmacokinetics, metabolism,
pharmacodynamics, dose response, safety, efficacy, and other pharmacological activities.
Where possible, a summary of each completed clinical trial should be provided.
Information should also be provided regarding results of any use of the
investigational product(s) other than from in clinical trials, such as from experience
during marketing.
(a) Pharmacokinetics and Product Metabolism in Humans
A summary of information on the pharmacokinetics of the investigational
product(s) should be presented, including the following, if available:
- Pharmacokinetics (including metabolism, as appropriate, and absorption,
plasma protein binding, distribution, and elimination).
- Bioavailability of the investigational product (absolute, where possible,
and/or relative) using a reference dosage form.
- Population subgroups (e.g., gender, age, and impaired organ function).
- Interactions (e.g., product-product interactions and effects of food).
- Other pharmacokinetic data (e.g., results of population studies performed
within clinical trial(s).
(b) Safety and Efficacy
A summary of information should be provided about the investigational
product's/products' (including metabolites, where appropriate) safety,
pharmacodynamics, efficacy, and dose response that were obtained from
preceding trials in humans (healthy volunteers and/or patients). The implications
of this information should be discussed. In cases where a number of clinical
trials have been completed, the use of summaries of safety and efficacy across
multiple trials by indications in subgroups may provide a clear presentation of the
data. Tabular summaries of adverse drug reactions for all the clinical trials
(including those for all the studied indications) would be useful. Important
47
Contains Nonbinding Recommendations
differences in adverse drug reaction patterns/incidences across indications or
subgroups should be discussed.
The IB should provide a description of the possible risks and adverse drug reactions
to be anticipated on the basis of prior experiences with the product under
investigation and with related products. A description should also be provided of
the precautions or special monitoring to be done as part of the investigational use
of the product(s).
(c) Marketing Experience
The IB should identify countries where the investigational product has been
marketed or approved. Any significant information arising from the marketed use
should be summarized (e.g., formulations, dosages, routes of administration, and
adverse product reactions). The IB should also identify all the countries where the
investigational product did not receive approval/registration for marketing or was
withdrawn from marketing/registration.
7.3.7
Summary of Data and Guidance for the Investigator
This section should provide an overall discussion of the nonclinical and clinical data,
and should summarize the information from various sources on different aspects of
the investigational product(s), wherever possible. In this way, the investigator can
be provided with the most informative interpretation of the available data and with an
assessment of the implications of the information for future clinical trials.
Where appropriate, the published reports on related products should be discussed.
This could help the investigator to anticipate adverse drug reactions or other problems
in clinical trials.
The overall aim of this section is to provide the investigator with a clear understanding of
the possible risks and adverse reactions, and of the specific tests, observations, and
precautions that may be needed for a clinical trial. This understanding should be based
on the available physical, chemical, pharmaceutical, pharmacological, toxicological, and
clinical information on the investigational product(s). Guidance should also be provided
to the clinical investigator on the recognition and treatment of possible overdose and
adverse drug reactions that are based on previous human experience and on the
pharmacology of the investigational product.
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Contains Nonbinding Recommendations
7.4
APPENDIX l
TITLE PAGE (Example)
SPONSOR'S NAME Product:
Research Number:
Name(s):
Chemical, Generic (if approved)
Trade Name(s) (if legally permissible and desired by the sponsor)
INVESTIGATOR'S BROCHURE
Edition Number:
Release Date:
Replaces Previous Edition Number:
Date:
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Contains Nonbinding Recommendations
7.5
APPENDIX 2
TABLE OF CONTENTS OF INVESTIGATOR'S BROCHURE (Example)
-
Confidentiality Statement (optional)
-
Signature Page (optional)
1.
Table of Contents
2.
Summary
3.
Introduction
4.
Physical, Chemical, and Pharmaceutical Properties and Formulation
5.
Nonclinical Studies
5.1
Nonclinical Pharmacology
5.2
Pharmacokinetics and Product Metabolism in Animals
5.3
Toxicology
6.
Effects in Humans.
6.1
Pharmacokinetics and Product Metabolism in Humans
6.2
Safety and Efficacy
6.3
Marketing Experience
7.
Summary of Data and Guidance for the Investigator
NB: References on
1. Publications
2. Reports
These references should be found at the end of each chapter.
Appendices (if any)
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Contains Nonbinding Recommendations
8.
ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL
8.l
Introduction
Essential Documents are those documents that individually and collectively permit evaluation of the conduct of a trial and the quality of the data
produced. These documents serve to demonstrate the compliance of the investigator, sponsor, and monitor with the standards of GCP and with
all applicable regulatory requirements.
Essential Documents also serve a number of other important purposes. Filing essential documents at the investigator/institution and sponsor sites in
a timely manner can greatly assist in the successful management of a trial by the investigator, sponsor, and monitor. These documents are also the
ones t h a t are usually audited by the sponsor's independent audit function and inspected by the regulatory authority(ies) as part of the
process to confirm the validity of the trial conduct and the integrity of data collected.
The minimum list of essential documents that has been developed follows. The various documents are grouped in three sections according to the
stage of the trial during which they will normally be generated: (1) before the clinical phase of the trial commences, ( 2 ) during the clinical
conduct of the trial, and (3) after completion or termination of the trial. A description is given of the purpose of each document, and whether it
should be filed in either the investigator/institution or sponsor files, or both. It is acceptable to combine some of the documents, provided the
individual elements are readily identifiable.
Trial master files should be established at the beginning of the trial, both at the investigator/institution's site and at the sponsor's office. A final
close-out of a trial can only be done when the monitor has reviewed both investigator/institution and sponsor files and confirmed that all
necessary documents are in the appropriate files.
Any or all of the documents addressed in this guidance may be subject to, and should be available for, audit by the sponsor's auditor and
inspection by the regulatory authority(ies).
ADDENDUM
The sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source
documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should provide for document
identification, version history, search, and retrieval.
Essential documents for the trial should be supplemented or may be reduced where justified (in advance of trial initiation), based on the importance
and relevance of the specific documents to the trial.
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Contains Nonbinding Recommendations
The sponsor should ensure that the investigator has control of and continuous access to the CRF data reported to the sponsor. The sponsor should not
have exclusive control of those data.
When a copy is used to replace an original document (e.g., source documents, CRF), the copy should fulfill the requirements for certified copies.
The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and
after the trial.
8.2
Before the Clinical Phase of the Trial Commences
During this planning stage the following documents should be generated and should be on file before the trial formally starts.
Title of Document
Purpose
Located in Files of
Investigator/Institution
Sponsor
X
X
8.2.1
INVESTIGATOR’S BROCHURE
To document that relevant and
current scientific information about
the investigational product has been
provided to the investigator
8.2.2
SIGNED PROTOCOL AND AMENDMENTS, IF
ANY, AND SAMPLE CASE REPORT FORM
(CRF)
To document investigator and
sponsor agreement to the
protocol/amendment(s) and CRF
X
X
8.2.3
INFORMATION GIVEN TO TRIAL SUBJECT
- INFORMED CONSENT FORM (including
all applicable translations)
To document the informed consent
X
X
X
-
ANY OTHER WRITTEN INFORMATION
To document that subjects will be
given appropriate written
information (content and wording)
to support their ability to give fully
informed consent
X
-
ADVERTISEMENT FOR SUBJECT
RECRUITMENT (if used)
To document that recruitment
measures are appropriate and not
coercive
X
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Contains Nonbinding Recommendations
8.2.4
FINANCIAL ASPECTS OF THE TRIAL
To document the financial
agreement between the
investigator/institution and the
sponsor for the trial
X
X
8.2.5
INSURANCE STATEMENT (where required)
To document that compensation to
subject(s) for trial-related injury
will be available
X
X
8.2.6
SIGNED AGREEMENT BETWEEN INVOLVED
PARTIES, e.g.:
- Investigator/institution and sponsor
- Investigator/institution and CRO
To document agreements
X
X
X
X
Sponsor and CRO
Investigator/institution and authority(ies)
(where required)
DATED, DOCUMENTED
APPROVAL/FAVORABLE OPINION OF
INSTITUTIONAL REVIEW BOARD
(IRB)/INDEPENDENT ETHICS COMMITTEE
(IEC) OF THE FOLLOWING:
• Protocol and any amendments
• CRF (if applicable)
• Informed consent form(s)
• Any other written information to be provided
to the subject(s)
• Advertisement for subject recruitment (if used)
• Subject compensation (if any)
• Any other documents given approval/favorable
opinion
-
8.2.7
To document that the trial has been
subject to IRB/IEC review and
given approval/favorable opinion.
To identify the version number and
date of the document(s)
53
(where required)
X
X
X
X
X
Contains Nonbinding Recommendations
8.2.8
INSTITUTIONAL REVIEW
BOARD/INDEPENDENT ETHICS COMMITTEE
COMPOSITION
8.2.9
REGULATORY AUTHORITY(IES)
To document appropriate
AUTHORIZATION/APPROVAL/NOTIFICATION authorization/approval/notification
OF PROTOCOL (where required)
by the regulatory authority(ies) has
been obtained prior to initiation of
the trial in compliance with the
applicable regulatory requirement(s)
8.2.10
CURRICULUM VITAE AND/OR OTHER
RELEVANT DOCUMENTS EVIDENCING
QUALIFICATIONS OF INVESTIGATOR(S) AND
SUBINVESTIGATOR(S)
8.2.11
To document that the IRB/IEC is
constituted in agreement with GCP
X
X
X
(where required)
X
(where required)
(where required)
To document qualifications and
eligibility to conduct trial and/or
provide medical supervision of
subjects
X
X
NORMAL VALUE(S)/RANGE(S) FOR
MEDICAL/LABORATORY/TECHNICAL
PROCEDURES(S) AND/OR TEST(S) INCLUDED
IN THE PROTOCOL
To document normal values and/or
ranges of the tests
X
X
8.2.12
MEDICAL/LABORATORY/TECHNICAL
PROCEDURES/TESTS
- Certification or
- Accreditation or
- Established quality control and/or external
quality assessment or
- Other validation (where required)
To document competence of facility
to perform required test(s), and
support reliability of results
X
X
8.2.13
SAMPLE OF LABEL(S) ATTACHED TO
INVESTIGATIONAL PRODUCT CONTAINER(S)
To document compliance with
applicable labelling regulations and
appropriateness of instructions
provided to the subjects
54
(where required)
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Contains Nonbinding Recommendations
8.2.14
INSTRUCTIONS FOR HANDLING OF
INVESTIGATIONAL PRODUCT(S) AND TRIALRELATED MATERIALS (if not included in
protocol or Investigator’s Brochure)
To document instructions needed to
ensure proper storage, packaging,
dispensing, and disposition of
investigational product(s) and trialrelated materials
X
X
8.2.15
SHIPPING RECORDS FOR INVESTIGATIONAL
PRODUCT(S) AND TRIAL-RELATED
MATERIALS
X
X
8.2.16
CERTIFICATE(S) OF ANALYSIS OF
INVESTIGATIONAL PRODUCT(S) SHIPPED
To document shipment dates, batch
numbers and method of shipment of
investigational product(s) and trialrelated materials. Allows tracking of
product batch, review of shipping
conditions, and accountability
To document identity, purity, and
strength of investigational
product(s) to be used in the trial
8.2.17
DECODING PROCEDURES FOR BLINDED
TRIALS
To document how, in case of an
emergency, identity of blinded
investigational product can be
revealed without breaking the blind
for the remaining subjects’
treatment
X
8.2.18
MASTER RANDOMIZATION LIST
To document method for
randomization of trial population
8.2.19
PRE-TRIAL MONITORING REPORT
To document that the site is suitable
for the trial (may be combined with
8.2.20)
8.2.20
TRIAL INITIATION MONITORING REPORT
To document that trial procedures
were reviewed with the investigator
and the investigator’s trial staff
(may be combined with 8.2.19)
55
X
X
(third party if
applicable)
X
(third party if
applicable)
X
X
X
Contains Nonbinding Recommendations
8.3
During the Clinical Conduct of the Trial
In addition to having on file the above documents, the following should be added to the files during the trial as evidence that all new relevant information is
documented as it becomes available.
Title of Document
Purpose
Located in Files of
Investigator/Institution
Sponsor
X
X
8.3.1
INVESTIGATOR’S BROCHURE UPDATES
To document that investigator
is informed in a timely manner
of relevant information as it
becomes available
8.3.2
ANY REVISION TO:
- Protocol/amendment(s) and CRF
- Informed consent form
- Any other written information provided to subjects
- Advertisement for subject recruitment (if used)
To document revisions of these
trial related documents that
take effect during trial
X
X
8.3.3
DATED, DOCUMENTED APPROVAL/FAVORABLE
OPINION OF INSTITUTIONAL REVIEW BOARD
IRB)/INDEPENDENT ETHICS COMMITTEE (IEC)
OF THE FOLLOWING:
To document that the
amendment(s) and/or
revision(s) have been subject to
IRB/IEC review and were
given approval/favorable
opinion. To identify the
version number and date of the
document(s).
X
X
•
•
•
•
Protocol amendment(s)
Revision(s) of:
− Informed consent form
− Any other written information to be
provided to the subject
− Advertisement for subject recruitment (if
used)
Any other documents given approval/favorable
opinion
Continuing review of trial (where required)
56
Contains Nonbinding Recommendations
8.3.4
REGULATORY AUTHORITY(IES)
To document compliance with
AUTHORIZATIONS/APPROVALS/NOTIFICATIONS applicable regulatory
WHERE REQUIRED FOR:
requirements
• Protocol amendment(s) and other documents
8.3.5
CURRICULUM VITAE FOR NEW
INVESTIGATOR(S) AND/OR
SUBINVESTIGATOR(S)
8.3.6
8.3.7
X
X
(See 8.2.10)
X
X
UPDATES TO NORMAL VALUE(S)/RANGE(S) FOR
MEDICAL/LABORATORY/TECHNICAL
PROCEDURE(S)/TEST(S) INCLUDED IN THE
PROTOCOL
To document normal values
and ranges that are revised
during the trial (see 8.2.11)
X
X
UPDATES OF
MEDICAL/LABORATORY/TECHNICAL
PROCEDURES/TESTS
To document that tests remain
adequate throughout the trial
period (see 8.2.12)
X
X
X
X
-
(where required)
(where required)
Certification or
Accreditation or
Established quality control and/or external quality
assessment or
Other validation (where required)
8.3.8
DOCUMENTATION OF INVESTIGATIONAL
PRODUCT(S) AND TRIAL-RELATED MATERIALS
SHIPMENT
(See 8.2.15)
8.3.9
CERTIFICATE(S) OF ANALYSIS FOR NEW
BATCHES OF INVESTIGATIONAL PRODUCTS
(See 8.2.16)
X
8.3.10
MONITORING VISIT REPORTS
To document site visits by, and
findings of, the monitor
X
57
Contains Nonbinding Recommendations
8.3.11
RELEVANT COMMUNICATIONS OTHER THAN
SITE VISITS
- Letters
- Meeting notes
- Notes of telephone calls
To document any agreements
or significant discussions
regarding trial administration,
protocol violations, trial
conduct, adverse event (AE)
reporting
X
8.3.12
SIGNED INFORMED CONSENT FORMS
To document that consent is
obtained in accordance with
GCP and protocol and dated
prior to participation of each
subject in trial. Also to
document direct access
permission (see 8.2.3)
X
8.3.13
SOURCE DOCUMENTS
To document the existence of
the subject and substantiate
integrity of trial data collected.
To include original documents
related to the trial, to medical
treatment, and history of
subject
X
8.3.14
SIGNED, DATED, AND COMPLETED CASE
REPORT FORMS (CRF)
To document that the
investigator or authorized
member of the investigator’s
staff confirms the observations
recorded
8.3.15
DOCUMENTATION OF CRF CORRECTIONS
To document all
changes/additions or
corrections made to CRF after
initial data were recorded
8.3.16
NOTIFICATION BY ORIGINATING
INVESTIGATOR TO SPONSOR OF SERIOUS
ADVERSE EVENTS AND RELATED REPORTS
Notification by originating
investigator to sponsor of
serious adverse events and
related reports in accordance
58
X
(copy)
X
X
X
(original)
X
(copy)
(original)
X
X
Contains Nonbinding Recommendations
with 4.11
8.3.17
NOTIFICATION BY SPONSOR AND/OR
INVESTIGATOR, WHERE APPLICABLE, TO
REGULATORY AUTHORITY(IES) AND
IRB(S)/IEC(S) OF UNEXPECTED SERIOUS
ADVERSE DRUG REACTIONS AND OF OTHER
SAFETY INFORMATION
8.3.18
NOTIFICATION BY SPONSOR TO
INVESTIGATORS OF SAFETY INFORMATION
8.3.19
INTERIM OR ANNUAL REPORTS TO IRB/IEC AND
AUTHORITY(IES)
Interim or annual reports
provided to IRB/IEC in
accordance with 4.10 and to
authority(ies) in accordance
with 5.17.3
X
8.3.20
SUBJECT SCREENING LOG
To document identification of
subjects who entered pre-trial
screening
X
8.3.21
SUBJECT IDENTIFICATION CODE LIST
To document that
investigator/institution keeps a
confidential list of names of all
subjects allocated to trial
numbers on enrolling in the
trial. Allows
investigator/institution to reveal
identity of any subject
X
8.3.22
SUBJECT ENROLMENT LOG
To document chronological
enrolment of subjects by trial
X
Notification by sponsor and/or
investigator, where applicable,
to regulatory authorities and
IRB(s)/IEC(s) of unexpected
serious adverse drug reactions
in accordance with 5.17 and
4.11.1 and of other safety
information in accordance with
5.16.2 and 4.11.2
Notification by sponsor to
investigators of safety
information in accordance with
5.16.2
59
X
X
X
X
(where required)
X
(where required)
X
(where required)
Contains Nonbinding Recommendations
number
8.3.23
INVESTIGATION PRODUCTS ACCOUNTABILITY
AT THE SITE
To document that
investigational product(s) have
been used according to the
protocol
X
X
8.3.24
SIGNATURE SHEET
To document signatures and
initials of all persons
authorized to make entries
and/or corrections on CRFs
X
X
8.3.25
RECORD OF RETAINED BODY FLUIDS/TISSUE
SAMPLES (IF ANY)
To document location and
identification of retained
samples if assays need to be
repeated
X
X
60
Contains Nonbinding Recommendations
8.4
After Completion or Termination of the Trial
After completion or termination of the trial, all of the documents identified in Sections 8.2 and 8.3 should be in the file together with the following
Title of Document
Purpose
Located in Files of
Investigator/Institution
Sponsor
X
X
8.4.1
INVESTIGATIONAL PRODUCT(S)
ACCOUNTABILITY AT SITE
To document that the
investigational product(s) have
been used according to the
protocol. To document the final
accounting of investigational
product(s) received at the site,
dispensed to subjects, returned
by the subjects, and returned to
sponsor
8.4.2
DOCUMENTATION OF
INVESTIGATIONAL PRODUCT
DESTRUCTION
To document destruction of
unused investigational products
by sponsor or at site
8.4.3
COMPLETED SUBJECT
IDENTIFICATION CODE LIST
To permit identification of all
subjects enrolled in the trial in
case follow-up is required. List
should be kept in a confidential
manner and for agreed upon time
8.4.4
AUDIT CERTIFICATE (if available)
To document that audit was
performed
X
8.4.5
FINAL TRIAL CLOSE-OUT
MONITORING REPORT
To document that all activities
required for trial close-out are
completed, and copies of
essential documents are held in
the appropriate files
X
61
X
(if destroyed at site)
X
X
Contains Nonbinding Recommendations
8.4.6
TREATMENT ALLOCATION AND
DECODING DOCUMENTATION
Returned to sponsor to document
any decoding that may have
occurred
8.4.7
FINAL REPORT BY INVESTIGATOR
TO IRB/IEC WHERE REQUIRED,
AND WHERE APPLICABLE, TO THE
REGULATORY AUTHORITY(IES)
To document completion of the
trial
8.4.8
CLINICAL STUDY REPORT
To document results and
interpretation of trial
62
X
X
X
(if applicable)
X
Contains Nonbinding Recommendations
9. PAPERWORK REDUCTION ACT OF 1995
This guidance contains information collection provisions that are subject to review by the Office of
Management and Budget (OMB) under the Paperwork Reduction Act of 1995 (44 U.S.C.
3501-3520).
The time required to complete this information collection is estimated to average 60 hours per
response to develop a quality management system, and 3 hours per response to report to FDA.
These estimates include the time to review instructions, search existing data sources, gather the data
needed, and complete and review the information collection. Send comments regarding this
burden estimate or suggestions for reducing this burden to:
Office of Medical Policy, Center for Drug Evaluation and Research, Food and Drug
Administration, 10903 New Hampshire Ave, Bldg. 51, Rm. 6337, Silver Spring, MD 209930002.
This guidance also refers to previously approved collections of information found in FDA
regulations. The collections of information found in 21 CFR part 11 have been approved under OMB
control number 0910-0303; the collections of information found in 21 CFR part 56 have been
approved under OMB control number 0910-07555; the collections of information found in 21 CFR
part 312 have been approved under OMB control numbers 0910-0014 and 0910-0733; the collections
of information found in 21 CFR part 314 have been approved under OMB control number 09100001; and the collections of information found in 21 CFR part 601 have been approved under OMB
control number 0910-0338.
An agency may not conduct or sponsor, and a person is not required to respond to, a collection of
information unless it displays a currently valid OMB control number. The OMB control number
for this information collection is 0910-0843. The current expiration date is available at
https://www.reginfo.gov (search ICR and enter OMB control number 0910-0843).
63
| File Type | application/pdf |
| File Title | Guidance for Industry: E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) |
| Subject | Guidance |
| Author | FDA/CDER |
| File Modified | 2022-11-09 |
| File Created | 2022-11-04 |