INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICALREQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE (ICH)ICH HARMONISED GUIDELINEINTEGRATED ADDENDUM TO ICH E6(R1):
GUIDELINE FOR GOOD CLINICAL PRACTICE
E6(R2)

Current Step 4 version
dated 9 November 2016

E6(R1)Document History

First
Codification

New
Codification
November
2005

History

Date

E6

Approval by the Steering Committee under Step 2
and release for public consultation.

27
April
1995

E6

E6

Approval by the Steering Committee under Step 4
and recommended for adoption to the three ICH
regulatory bodies.

1
May
1996

E6

10
June
1996

E6(R1)

E6(R1) Step 4 version
E6

Code
E6(R2)

Approval by the Steering Committee of Post-Step 4
editorial corrections.

Current E6(R2) Addendum Step 4 version
History
Adoption by the Regulatory Members of the ICH Assembly
under Step 4.

Date
9 November
2016

Integrated Addendum to ICH E6(R1) document. Changes areintegrated directly into the following sections of the parental
Guideline: Introduction, 1.63, 1.64, 1.65, 2.10, 2.13, 4.2.5, 4.2.6,
4.9.0, 5.0, 5.0.1, 5.0.2, 5.0.3, 5.0.4, 5.0.5, 5.0.6, 5.0.7, 5.2.2,
5.5.3 (a), 5.5.3 (b), 5.5.3 (h), 5.18.3, 5.18.6 (e), 5.18.7, 5.20.1,
8.1
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ICH HARMONISED GUIDELINEINTEGRATED ADDENDUM TO ICH E6(R1): GUIDELINE FOR
GOOD CLINICAL PRACTICE ICH
E6(R2)ICH Consensus Guideline
TABLE OF CONTENTSINTRODUCTION.......................................................................................................... 1
1.

GLOSSARY ......................................................................................................... 2

2.

THE PRINCIPLES OF ICH GCP .......................................................................... 93.

INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE(IRB/IEC) .......................................................................................................... 10

3.1

Responsibilities ........................................................................................................ 10

3.2

Composition, Functions and Operations ...................................................................... 11

3.3

Procedures............................................................................................................... 11

3.4

Records ................................................................................................................... 12

4.

INVESTIGATOR ............................................................................................... 13

4.1

Investigator's Qualifications and Agreements ............................................................... 13

4.2

Adequate Resources ................................................................................................. 13

4.3

Medical Care of Trial Subjects ................................................................................... 14

4.4

Communication with IRB/IEC ................................................................................... 14

4.5

Compliance with Protocol ......................................................................................... 14

4.6

Investigational Product(s) .......................................................................................... 15

4.7

Randomization Procedures and Unblinding ................................................................. 15

4.8

Informed Consent of Trial Subjects ............................................................................ 16

4.9

Records and Reports ................................................................................................. 19

4.10 Progress Reports ...................................................................................................... 19
4.11 Safety Reporting ...................................................................................................... 20
4.12 Premature Termination or Suspension of a Trial ........................................................... 20
4.13 Final Report(s) by Investigator ................................................................................... 20
5.

SPONSOR ......................................................................................................... 21

5.0

Quality Management ................................................................................................ 21

5.1

Quality Assurance and Quality Control ....................................................................... 22

5.2

Contract Research Organization (CRO)....................................................................... 22

5.3

Medical Expertise..................................................................................................... 23iIntegrated Addendum to E6(R1): Guideline for Good Clinical Practice

5.4

Trial Design............................................................................................................. 23

5.5

Trial Management, Data Handling, and Record Keeping ............................................... 23

5.6

Investigator Selection ............................................................................................... 25

5.7

Allocation of Responsibilities .................................................................................... 25

5.8

Compensation to Subjects and Investigators ................................................................ 25

5.9

Financing ................................................................................................................ 26

5.10 Notification/Submission to Regulatory Authority(ies) ................................................... 26
5.11 Confirmation of Review by IRB/IEC .......................................................................... 26
5.12 Information on Investigational Product(s) .................................................................... 26
5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s) .................. 27
5.14 Supplying and Handling Investigational Product(s) ...................................................... 27
5.15 Record Access ......................................................................................................... 28
5.16 Safety Information.................................................................................................... 28
5.17 Adverse Drug Reaction Reporting .............................................................................. 28
5.18 Monitoring .............................................................................................................. 29
5.18.1

Purpose ............................................................................................................... 29

5.18.2

Selection and Qualifications of Monitors .......................................................... 29

5.18.3Extent and Nature of Monitoring ....................................................................... 29

5.18.5

Monitoring Procedures....................................................................................... 31

5.18.6

Monitoring Report.............................................................................................. 32

5.18.7

Monitoring Plan ................................................................................................. 32

5.19 Audit ...................................................................................................................... 32
5.19.1

Purpose ............................................................................................................... 32

5.19.2

Selection and Qualification of Auditors ............................................................. 32

5.19.3

Auditing Procedures ........................................................................................... 33

5.20 Noncompliance ........................................................................................................ 33
5.21 Premature Termination or Suspension of a Trial ........................................................... 33
5.22 Clinical Trial/Study Reports ...................................................................................... 33
5.23 Multicentre Trials ..................................................................................................... 34
6.

CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S) ................ 34

6.1

General Information ................................................................................................. 34

6.2

Background Information ........................................................................................... 35

6.3

Trial Objectives and Purpose ..................................................................................... 35

6.4

Trial Design............................................................................................................. 35

6.5

Selection and Withdrawal of Subjects ......................................................................... 36

6.6

Treatment of Subjects ............................................................................................... 36

6.7

Assessment of Efficacy ............................................................................................. 36ii

Integrated Addendum to E6(R1): Guideline for Good Clinical Practice

6.8

Assessment of Safety ................................................................................................ 36

6.9

Statistics.................................................................................................................. 37

6.10 Direct Access to Source Data/Documents .................................................................... 37
6.11 Quality Control and Quality Assurance ....................................................................... 37
6.12 Ethics ..................................................................................................................... 37
6.13 Data Handling and Record Keeping ............................................................................ 37
6.14 Financing and Insurance............................................................................................ 37
6.15 Publication Policy .................................................................................................... 37
6.16 Supplements ............................................................................................................ 37
7.

INVESTIGATOR’S BROCHURE........................................................................ 38

7.1

Introduction ............................................................................................................. 38

7.2

General Considerations ............................................................................................. 38

7.3

7.2.1

Title Page ........................................................................................................... 38

7.2.2

Confidentiality Statement .................................................................................. 39

Contents of the Investigator’s Brochure ...................................................................... 39
7.3.1

Table of Contents ............................................................................................... 39

7.3.2

Summary ............................................................................................................ 39

7.3.3

Introduction ........................................................................................................ 39

7.3.4

Physical, Chemical, and Pharmaceutical Properties and Formulation ............... 39

7.3.5

Nonclinical Studies ............................................................................................ 39

7.3.6

Effects in Humans .............................................................................................. 41

7.3.7

Summary of Data and Guidance for the Investigator ......................................... 42

7.4

APPENDIX 1: ......................................................................................................... 43

7.5

APPENDIX 2: ......................................................................................................... 448.

ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL ....... 45

8.1

Introduction ............................................................................................................. 45

8.2

Before the Clinical Phase of the Trial Commences ....................................................... 46

8.3

During the Clinical Conduct of the Trial ..................................................................... 53

8.4

After Completion or Termination of the Trial .............................................................. 59

iii

INTEGRATED ADDENDUM TO ICH E6(R1): GUIDELINE FOR
GOOD CLINICAL PRACTICE ICH
E6(R2)INTRODUCTION
Good Clinical Practice (GCP) is an international ethical and scientific quality standard fordesigning, conducting, recording and reporting trials that involve the participation of humansubjects. Compliance with this standard provides public assurance that the rights, safety andwell-being of trial subjects are protected, consistent with the principles that have their origin
in the Declaration of Helsinki, and that the clinical trial data are credible.
The objective of this ICH GCP Guideline is to provide a unified standard for the European
Union (EU), Japan and the United States to facilitate the mutual acceptance of clinical databy the regulatory authorities in these jurisdictions.
The guideline was developed with consideration of the current good clinical practices of theEuropean Union, Japan, and the United States, as well as those of Australia, Canada, theNordic countries and the World Health Organization (WHO).
This guideline should be followed when generating clinical trial data that are intended to besubmitted to regulatory authorities.
The principles established in this guideline may also be applied to other clinicalinvestigations that may have an impact on the safety and well-being of human subjects.
ADDENDUM
Since the development of the ICH GCP Guideline, the scale, complexity, and cost of clinical
trials have increased. Evolutions in technology and risk management processes offer newopportunities to increase efficiency and focus on relevant activities. When the original ICH
E6(R1) text was prepared, clinical trials were performed in a largely paper-based process.
Advances in use of electronic data recording and reporting facilitate implementation of otherapproaches. For example, centralized monitoring can now offer a greater advantage, to abroader range of trials than is suggested in the original text. Therefore, this guideline has
been amended to encourage implementation of improved and more efficient approaches toclinical 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 havealso been updated.
This guideline should be read in conjunction with other ICH guidelines 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 Guideline Integrated Addendum provides a unified standard for the European
Union, Japan, the United States, Canada, and Switzerland to facilitate the mutual acceptanceof 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.

1

1.

GLOSSARY

1.1
Adverse Drug Reaction (ADR)
In the pre-approval clinical experience with a new medicinal product or its new usages,
particularly as the therapeutic dose(s) may not be established: all noxious and unintended
responses to a medicinal product related to any dose should be considered adverse drug
reactions. The phrase responses to a medicinal product means that a causal relationship between
a medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationshipcannot 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 apharmaceutical product and which does not necessarily have a causal relationship with thistreatment. An adverse event (AE) can therefore be any unfavourable and unintended sign(including an abnormal laboratory finding), symptom, or disease temporally associated with theuse of a medicinal (investigational) product, whether or not related to the medicinal(investigational) product (see the ICH Guideline for Clinical Safety Data Management:
Definitions and Standards for Expedited Reporting).
1.3
Amendment (to the protocol)
See Protocol Amendment.
1.4
Applicable Regulatory Requirement(s)Any law(s) and regulation(s) addressing the conduct of clinical trials of investigational products.
1.5
Approval (in relation to Institutional Review Boards)
The affirmative decision of the IRB that the clinical trial has been reviewed and may be
conducted at the institution site within the constraints set forth by the IRB, the institution, Good
Clinical Practice (GCP), and the applicable regulatory requirements.
1.6
Audit
A systematic and independent examination of trial related activities and documents to determine
whether the evaluated trial related activities were conducted, and the data were recorded,
analyzed and accurately reported according to the protocol, sponsor's standard operatingprocedures (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.

2

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

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, pharmacologicaland/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, andanalyses are fully integrated into a single report (see the ICH Guideline for Structure and Content
of Clinical Study Reports).
1.14 Comparator (Product)
An investigational or marketed product (i.e., active control), or placebo, used as a reference in aclinical trial.
1.15 Compliance (in relation to trials)
Adherence to all the trial-related requirements, Good Clinical Practice (GCP) requirements, andthe applicable regulatory requirements.
1.16 Confidentiality
Prevention of disclosure, to other than authorized individuals, of a sponsor's proprietary
information or of a subject's identity.
1.17 Contract
A written, dated, and signed agreement between two or more involved parties that sets out any
arrangements on delegation and distribution of tasks and obligations and, if appropriate, on
financial matters. The protocol may serve as the basis of a contract.
1.18 Coordinating Committee
A committee that a sponsor may organize to coordinate the conduct of a multicentre trial.
1.19 Coordinating Investigator
An investigator assigned the responsibility for the coordination of investigators at different
centres participating in a multicentre trial.

3

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

1.20 Contract Research Organization (CRO)A person or an organization (commercial, academic, or other) contracted by the sponsor toperform one or more of a sponsor's trial-related duties and functions.
1.21 Direct Access
Permission to examine, analyze, verify, and reproduce any records and reports that are importantto 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 ofsubjects' identities and sponsor’s proprietary information.
1.22 Documentation
All records, in any form (including, but not limited to, written, electronic, magnetic, and optical
records, and scans, x-rays, and electrocardiograms) that describe or record the methods, conduct,
and/or results of a trial, the factors affecting a trial, and the actions taken.
1.23 Essential Documents
Documents which individually and collectively permit evaluation of the conduct of a study andthe quality of the data produced (see 8. Essential Documents for the Conduct of a Clinical Trial).
1.24 Good Clinical Practice (GCP)
A standard for the design, conduct, performance, monitoring, auditing, recording, analyses, andreporting 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 atintervals the progress of a clinical trial, the safety data, and the critical efficacy endpoints, and torecommend 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 otherwritten information supplied to the subject.
1.27 Independent Ethics Committee (IEC)
An independent body (a review board or a committee, institutional, regional, national, or
supranational), constituted of medical professionals and non-medical members, whose
responsibility it is to ensure the protection of the rights, safety and well-being of human subjects
involved in a trial and to provide public assurance of that protection, by, among other things,
reviewing and approving/providing favourable opinion on, the trial protocol, the suitability of theinvestigator(s), facilities, and the methods and material to be used in obtaining and documenting
informed consent of the trial subjects.
The legal status, composition, function, operations and regulatory requirements pertaining to
Independent Ethics Committees may differ among countries, but should allow the Independent
Ethics Committee to act in agreement with GCP as described in this guideline.

4Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice1.28 Informed Consent
A process by which a subject voluntarily confirms his or her willingness to participate in aparticular trial, after having been informed of all aspects of the trial that are relevant to thesubject'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 researchorganization’s (CRO’s) facilities, or at other establishments deemed appropriate by theregulatory authority(ies).
1.30 Institution (medical)
Any public or private entity or agency or medical or dental facility where clinical trials are
conducted.
1.31 Institutional Review Board (IRB)
An independent body constituted of medical, scientific, and non-scientific members, whose
responsibility is to ensure the protection of the rights, safety and well-being of human subjects
involved in a trial by, among other things, reviewing, approving, and providing continuing
review of trial protocol and amendments and of the methods and material to be used in obtaining
and documenting informed consent of the trial subjects.
1.32 Interim Clinical Trial/Study Report
A report of intermediate results and their evaluation based on analyses performed during thecourse of a trial.
1.33 Investigational ProductA pharmaceutical form of an active ingredient or placebo being tested or used as a reference in aclinical 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 ateam 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 applicableregulatory requirements".
1.36 Investigator's Brochure
A compilation of the clinical and nonclinical data on the investigational product(s) which isrelevant to the study of the investigational product(s) in human subjects (see 7. Investigator’sBrochure).
1.37 Legally Acceptable Representative
An individual or juridical or other body authorized under applicable law to consent, on behalf ofa prospective subject, to the subject's participation in the clinical trial.

5Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice1.38 Monitoring
The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted,
recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs),
Good Clinical Practice (GCP), and the applicable regulatory requirement(s).
1.39

Monitoring Report

A written report from the monitor to the sponsor after each site visit and/or other trial-related
communication according to the sponsor’s SOPs.
1.40

Multicentre Trial

A clinical trial conducted according to a single protocol but at more than one site, and therefore,
carried out by more than one investigator.
1.41 Nonclinical Study
Biomedical studies not performed on human subjects.
1.42 Opinion (in relation to Independent Ethics Committee)
The judgement and/or the advice provided by an Independent Ethics Committee (IEC).
1.43 Original Medical Record
See Source Documents.
1.44 Protocol
A document that describes the objective(s), design, methodology, statistical considerations, andorganization of a trial. The protocol usually also gives the background and rationale for the trial,
but these could be provided in other protocol referenced documents. Throughout the ICH GCP
Guideline the term protocol refers to protocol and protocol amendments.
1.45 Protocol Amendment
A written description of a change(s) to or formal clarification of a protocol.
1.46 Quality Assurance (QA)
All those planned and systematic actions that are established to ensure that the trial is performed
and the data are generated, documented (recorded), and reported in compliance with Good
Clinical Practice (GCP) and the applicable regulatory requirement(s).
1.47 Quality Control (QC)
The operational techniques and activities undertaken within the quality assurance system toverify that the requirements for quality of the trial-related activities have been fulfilled.
1.48 Randomization
The process of assigning trial subjects to treatment or control groups using an element of chance
to determine the assignments in order to reduce bias.
1.49 Regulatory Authorities
Bodies having the power to regulate. In the ICH GCP Guideline the expression Regulatory
Authorities includes the authorities that review submitted clinical data and those that conduct
inspections (see 1.29). These bodies are sometimes referred to as competent authorities.

6Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice1.50 Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)
Any untoward medical occurrence that at any dose:- results in death,- is life-threatening,- requires inpatient hospitalization or prolongation of existing hospitalization,- results in persistent or significant disability/incapacity,or- is a congenital anomaly/birth defect(see the ICH Guideline for Clinical Safety Data Management: Definitions and Standards for
Expedited Reporting).
1.51 Source Data
All information in original records and certified copies of original records of clinical findings,
observations, or other activities in a clinical trial necessary for the reconstruction and evaluationof the trial. Source data are contained in source documents (original records or certified copies).
1.52 Source Documents
Original documents, data, and records (e.g., hospital records, clinical and office charts,
laboratory notes, memoranda, subjects' diaries or evaluation checklists, pharmacy dispensing
records, recorded data from automated instruments, copies or transcriptions certified after
verification as being accurate copies, microfiches, photographic negatives, microfilm or
magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories and at
medico-technical departments involved in the clinical trial).
1.53 Sponsor
An individual, company, institution, or organization which takes responsibility for the initiation,
management, and/or financing of a clinical trial.
1.54 Sponsor-Investigator
An individual who both initiates and conducts, alone or with others, a clinical trial, and underwhose immediate direction the investigational product is administered to, dispensed to, or usedby a subject. The term does not include any person other than an individual (e.g., it does notinclude a corporation or an agency). The obligations of a sponsor-investigator include both thoseof 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 ata 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.

7Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice1.58 Subject Identification CodeA 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 productinformation (e.g., Investigator's Brochure for an unapproved investigational product or package
insert/summary of product characteristics for an approved product) (see the ICH Guideline forClinical 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 pharmaceuticalindustry, members of the armed forces, and persons kept in detention. Other vulnerable subjects
include patients with incurable diseases, persons in nursing homes, unemployed or impoverishedpersons, patients in emergency situations, ethnic minority groups, homeless persons, nomads,
refugees, minors, and those incapable of giving consent.
1.62 Well-being (of the trial subjects)
The physical and mental integrity of the subjects participating in a clinical trial.
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 formonitoring 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 ortransition to a new system. The approach to validation should be based on a risk assessment thattakes into consideration the intended use of the system and the potential of the system to affecthuman subject protection and reliability of trial results.

8

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice2.

THE PRINCIPLES OF ICH GCP

2.1

Clinical trials should be conducted in accordance with the ethical principles that havetheir origin in the Declaration of Helsinki, and that are consistent with GCP and theapplicable regulatory requirement(s).

2.2Before a trial is initiated, foreseeable risks and inconveniences should be weighed against
the anticipated benefit for the individual trial subject and society. A trial should beinitiated 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 importantconsiderations 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 priorinstitutional
reviewboard(IRB)/independent
ethicscommittee(IEC)approval/favourable 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).

2.9Freely 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 guideline, irrespective of the typeof 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).

2.12Investigational products should be manufactured, handled, and stored in accordance withapplicable good manufacturing practice (GMP). They should be used in accordance withthe approved protocol.

9Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

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 oftrial 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'sBrochure (IB), available safety information, information about payments andcompensation 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 anddocument its views in writing, clearly identifying the trial, the documents reviewed andthe dates for the following:- approval/favourable opinion;- modifications required prior to its approval/favourable opinion;- disapproval / negative opinion; and- termination/suspension of any prior approval/favourable opinion.

3.1.3

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 judgement of the IRB/IEC, the additional information would add
meaningfully to the protection of the rights, safety and/or well-being of the subjects.

3.1.6

When a non-therapeutic trial is to be carried out with the consent of the subject’s legally
acceptable representative (see 4.8.12, 4.8.14), the IRB/IEC should determine that the
proposed protocol and/or other document(s) adequately addresses relevant ethicalconcerns and meets applicable regulatory requirements for such trials.

10Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

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 4.8.15), the IRB/IEC should determine thatthe proposed protocol and/or other document(s) adequately addresses relevant ethicalconcerns 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 toassure 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 thetrial by the subject.

3.1.9

The IRB/IEC should ensure that information regarding payment to subjects, including themethods, 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 havethe qualifications and experience to review and evaluate the science, medical aspects, andethics 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 aquorum, as stipulated in its written operating procedures, is present.

3.2.4

Only members who participate in the IRB/IEC review and discussion should
vote/provide their opinion and/or advise.

3.2.5

The investigator may provide information on any aspect of the trial, but should notparticipate 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:11

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

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 andapproval/favourable opinion of minor change(s) in ongoing trials that have theapproval/favourable 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/favourable opinion of the trial.

3.3.7

Specifying that no deviations from, or changes of, the protocol should be initiatedwithout prior written IRB/IEC approval/favourable opinion of an appropriate
amendment, except when necessary to eliminate immediate hazards to the subjects orwhen the change(s) involves only logistical or administrative aspects of the trial (e.g.,change of monitor(s), telephone number(s)) (see 4.5.2).

3.3.8

Specifying that the investigator should promptly report to the IRB/IEC:(a) Deviations from, or changes of, the protocol to eliminate immediate hazards to thetrial subjects (see 3.3.7, 4.5.2, 4.5.4).
(b) Changes increasing the risk to subjects and/or affecting significantly the conduct of
the trial (see 4.10.2).
(c) All adverse drug reactions (ADRs) that are both serious and unexpected.
(d) New information that may affect adversely the safety of the subjects or the conductof the trial.

3.3.9

Ensuring that the IRB/IEC promptly notify in writing the investigator/institution
concerning:(a) Its trial-related decisions/opinions.
(b) The reasons for its decisions/opinions.
(c) Procedures for appeal of its decisions/opinions.

3.4

Records

The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists, listsof occupations/affiliations of members, submitted documents, minutes of meetings, andcorrespondence) for a period of at least 3-years after completion of the trial and make themavailable 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.

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Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

4.

INVESTIGATOR

4.1

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 ofsuch qualifications through up-to-date curriculum vitae and/or other relevant
documentation requested by the sponsor, the IRB/IEC, and/or the regulatory
authority(ies).

4.1.2

The investigator should be thoroughly familiar with the appropriate use of theinvestigational product(s), as described in the protocol, in the current Investigator'sBrochure, in the product information and in other information sources provided by thesponsor.

4.1.3

The investigator should be aware of, and should comply with, GCP and the applicableregulatory requirements.

4.1.4

The investigator/institution should permit monitoring and auditing by the sponsor, andinspection by the appropriate regulatory authority(ies).

4.1.5

The investigator should maintain a list of appropriately qualified persons to whom theinvestigator 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.

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 andadequate facilities for the foreseen duration of the trial to conduct the trial properly andsafely.

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 trial-related duties
and functions.

ADDENDUM
4.2.5

The investigator is responsible for supervising any individual or party to whom theinvestigator 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 individualor 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.
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Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

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 forintercurrent 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/favourable opinion from the IRB/IEC for the trial protocol, written informed
consent form, consent form updates, subject recruitment procedures (e.g.,
advertisements), and any other written information to be provided to subjects.

4.4.2

As part of the investigator's/institution’s written application to the IRB/IEC, theinvestigator/institution should provide the IRB/IEC with a current copy of theInvestigator's Brochure. If the Investigator's Brochure is updated during the trial, theinvestigator/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 wasgiven approval/favourable opinion by the IRB/IEC. The investigator/institution and thesponsor 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/favourable
opinion from the IRB/IEC of an amendment, except where necessary to eliminate an
immediate hazard(s) to trial subjects, or when the change(s) involves only logistical oradministrative aspects of the trial (e.g., change in monitor(s), change of telephone
number(s)).

14Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

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 of, the protocol toeliminate an immediate hazard(s) to trial subjects without prior IRB/IEC
approval/favourable opinion. As soon as possible, the implemented deviation or change,
the reasons for it, and, if appropriate, the proposed protocol amendment(s) should besubmitted:(a) to the IRB/IEC for review and approval/favourable opinion,(b) to the sponsor for agreement and, if required,(c) to the regulatory authority(ies).

4.6

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 theinvestigator's/institution’s duties for investigational product(s) accountability at the trialsite(s) to an appropriate pharmacist or another appropriate individual who is under thesupervision of the investigator/institution..

4.6.3

The investigator/institution and/or a pharmacist or other appropriate individual, who isdesignated 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 returnto the sponsor or alternative disposition of unused product(s). These records should
include dates, quantities, batch/serial numbers, expiration dates (if applicable), and theunique 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 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 inaccordance with the approved protocol.

4.6.6

The investigator, or a person designated by the investigator/institution, should explain thecorrect 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 ensurethat the code is broken only in accordance with the protocol. If the trial is blinded, theinvestigator 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).

15Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

4.8

Informed Consent of Trial Subjects

4.8.1

In obtaining and documenting informed consent, the investigator should comply with theapplicable regulatory requirement(s), and should adhere to GCP and to the ethicalprinciples that have their origin in the Declaration of Helsinki. Prior to the beginning of
the trial, the investigator should have the IRB/IEC's written approval/favourable opinionof the written informed consent form and any other written information to be provided tosubjects.

4.8.2

The written informed consent form and any other written information to be provided tosubjects should be revised whenever important new information becomes available that
may be relevant to the subject’s consent. Any revised written informed consent form, andwritten information should receive the IRB/IEC's approval/favourable opinion in advanceof use. The subject or the subject’s legally acceptable representative should be informed
in a timely manner if new information becomes available that may be relevant to thesubject’s willingness to continue participation in the trial. The communication of thisinformation should be documented.

4.8.3

Neither the investigator, nor the trial staff, should coerce or unduly influence a subject toparticipate 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 theiragents from liability for negligence.

4.8.5

The investigator, or a person designated by the investigator, should fully inform thesubject or, if the subject is unable to provide informed consent, the subject's legally
acceptable representative, of all pertinent aspects of the trial including the written
information and the approval/ favourable opinion by the IRB/IEC.

4.8.6

The language used in the oral and written information about the trial, including thewritten informed consent form, should be as non-technical as practical and should beunderstandable to the subject or the subject's legally acceptable representative and theimpartial witness, where applicable.

4.8.7

Before informed consent may be obtained, the investigator, or a person designated by theinvestigator, 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 thesatisfaction 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 besigned 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. Afterthe written informed consent form and any other written information to be provided tosubjects, is read and explained to the subject or the subject’s legally acceptable

16

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practicerepresentative, and after the subject or the subject’s legally acceptable representative hasorally consented to the subject’s participation in the trial and, if capable of doing so, hassigned and personally dated the informed consent form, the witness should sign andpersonally 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 anyother written information to be provided to subjects should include explanations of thefollowing:(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, whenapplicable, to an embryo, fetus, or nursing infant.
(h) The reasonably expected benefits. When there is no intended clinical benefit to thesubject, the subject should be made aware of this.
(i) The alternative procedure(s) or course(s) of treatment that may be available to thesubject, and their important potential benefits and risks.
(j) The compensation and/or treatment available to the subject in the event of trialrelated 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 lossof 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 verificationof clinical trial procedures and/or data, without violating the confidentiality of thesubject, 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 ina timely manner if information becomes available that may be relevant to thesubject's willingness to continue participation in the trial.
17

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice(q) The person(s) to contact for further information regarding the trial and the rights oftrial subjects, and whom to contact in the event of trial-related injury.
(r) The foreseeable circumstances and/or reasons under which the subject's participationin the trial may be terminated.
(s) The expected duration of the subject's participation in the trial.
(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 beenrolled 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 thetrial 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 Non-therapeutic 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 can not be met by means of a trial in subjects who can giveinformed 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/favourable opinion of the IRB/IEC is expressly sought on the inclusionof such subjects, and the written approval/ favourable opinion covers this aspect.
Such trials, unless an exception is justified, should be conducted in patients having a
disease or condition for which the investigational product is intended. Subjects in thesetrials 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. Whenprior consent of the subject is not possible, and the subject’s legally acceptable
representative is not available, enrolment of the subject should require measuresdescribed in the protocol and/or elsewhere, with documented approval/favourable
opinion by the IRB/IEC, to protect the rights, safety and well-being of the subject and toensure compliance with applicable regulatory requirements. The subject or the subject's
legally acceptable representative should be informed about the trial as soon as possible

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Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practiceand consent to continue and other consent as appropriate (see 4.8.10) should berequested.
4.9

Records and Reports

ADDENDUM
4.9.0 The investigator/institution should maintain adequate and accurate source documents andtrial records that include all pertinent observations on each of the site’s trial subjects.
Source data should be attributable, legible, contemporaneous, original, accurate, andcomplete. 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 ofthe 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 (ifnecessary) and should not obscure the original entry (i.e., an audit trail should bemaintained); 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 designatedrepresentatives 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 8.) and as required by the applicableregulatory 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 amarketing 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 beretained (see 5.5.12).

4.9.6

The financial aspects of the trial should be documented in an agreement between thesponsor and the investigator/institution.

4.9.7

Upon request of the monitor, auditor, IRB/IEC, or regulatory authority, theinvestigator/institution should make available for direct access all requested trial-related
records.

4.10

Progress Reports

4.10.1 The investigator should submit written summaries of the trial status to the IRB/IEC
annually, or more frequently, if requested by the IRB/IEC.
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Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

4.10.2 The investigator should promptly provide written reports to the sponsor, the IRB/IEC(see 3.3.8) and, where applicable, the institution on any changes significantly affecting
the conduct of the trial, and/or increasing the risk to subjects.
4.11

Safety Reporting

4.11.1 All serious adverse events (SAEs) should be reported immediately to the sponsor except
for those SAEs that the protocol or other document (e.g., Investigator's Brochure)identifies as not needing immediate reporting. The immediate reports should be followed
promptly by detailed, written reports. The immediate and follow-up reports should
identify subjects by unique code numbers assigned to the trial subjects rather than by the
subjects' names, personal identification numbers, and/or addresses. The investigatorshould also comply with the applicable regulatory requirement(s) related to the reportingof 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 tosafety 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 forthe subjects, and, where required by the applicable regulatory requirement(s), should inform theregulatory 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 theinvestigator/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 orsuspension.
4.12.2 If the sponsor terminates or suspends a trial (see 5.21), the investigator should promptly
inform the institution where applicable and the investigator/institution should promptly
inform the IRB/IEC and provide the IRB/IEC a detailed written explanation of thetermination or suspension.
4.12.3 If the IRB/IEC terminates or suspends its approval/favourable opinion of a trial (see 3.1.2
and 3.3.9), the investigator should inform the institution where applicable and theinvestigator/institution should promptly notify the sponsor and provide the sponsor witha 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.

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Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice5.

SPONSORADDENDUM
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 thereliability of trial results. Quality management includes the design of efficient clinical trial
protocols and 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 therisks 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 thatare 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 beconsidered at both the system level (e.g., standard operating procedures, computerized
systems, personnel) and clinical trial level (e.g., trial design, data collection, informed
consent process).

5.0.3

Risk Evaluation
The sponsor should evaluate the identified risks, against existing risk controls byconsidering:(a) The likelihood of errors occurring.
(b) The extent to which such errors would be detectable.
(c) The impact of such errors on human subject protection and reliability of trial
results.

5.0.4

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 thesignificance of the risk. Risk reduction activities may be incorporated in protocol design
and implementation, monitoring plans, agreements between parties defining roles andresponsibilities, systematic safeguards to ensure adherence to standard operatingprocedures, 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 ofthe trial, to identify systematic issues that can impact subject safety or reliability of trial

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Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

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 bysuch 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 andremedial actions taken in the clinical study report (ICH E3, Section 9.6 Data Quality
Assurance).

5.1

Quality Assurance and Quality Control

5.1.1

The sponsor is responsible for implementing and maintaining quality assurance andquality 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 1.21) to all trial related sites, source data/documents , and reports forthe purpose of monitoring and auditing by the sponsor, and inspection by domestic andforeign regulatory authorities.

5.1.3

Quality control should be applied to each stage of data handling to ensure that all data arereliable 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 shouldbe specified in writing.

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Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

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 anotherparty 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 guideline also apply to a CRO to the extent that a CRO
has assumed the trial related duties and functions of a sponsor.

5.3

Medical Expertise

The sponsor should designate appropriately qualified medical personnel who will be readily
available to advise on trial related medical questions or problems. If necessary, outside
consultant(s) may be appointed for this purpose.
5.4

Trial Design

5.4.1

The sponsor should utilize qualified individuals (e.g., biostatisticians, clinicalpharmacologists, 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 6.), theICH Guideline for Structure and Content of Clinical Study Reports, and other appropriate
ICH guidance on trial design, protocol and conduct.

5.5

Trial Management, Data Handling, and Record Keeping

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 statisticalanalyses, 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, thesponsor should:(a) Ensure and document that the electronic data processing system(s) conforms to thesponsor’s established requirements for completeness, accuracy, reliability, andconsistent 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 thepotential of the system to affect human subject protection and reliability of trial
results.
23

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice(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 thesponsor, 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 thedata 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 4.1.5
and 4.9.3).
(f) Maintain adequate backup of the data.
(g) Safeguard the blinding, if any (e.g., maintain the blinding during data entry andprocessing).
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 thecomputerized 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 theoriginal 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-specificessential documents pertaining to the trial (see 8. Essential Documents for the Conduct ofa Clinical Trial).

5.5.7

The sponsor should retain all sponsor-specific essential documents in conformance withthe applicable regulatory requirement(s) of the country(ies) where the product isapproved, 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, thesponsor 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).

24Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

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 haveelapsed 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 forrecord retention and should notify the investigator(s)/institution(s) in writing when thetrial related records are no longer needed.
5.6

Investigator Selection

5.6.1

The sponsor is responsible for selecting the investigator(s)/institution(s). Eachinvestigator should be qualified by training and experience and should have adequate
resources (see 4.1, 4.2) to properly conduct the trial for which the investigator is selected.
If organization of a coordinating committee and/or selection of coordinating
investigator(s) are to be utilized in multicentre trials, their organization and/or selection
are the sponsor's responsibility.

5.6.2

Before entering an agreement with an investigator/institution to conduct a trial, thesponsor should provide the investigator(s)/institution(s) with the protocol and an up-todate Investigator's Brochure, and should provide sufficient time for theinvestigator/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 4.1.3), and with the protocol agreed to by the sponsor and given
approval/favourable opinion by the IRB/IEC (see 4.5.1);(b) to comply with procedures for data recording/reporting;(c) to permit monitoring, auditing and inspection (see 4.1.4) and(d) to retain the trial related essential documents until the sponsor informs theinvestigator/institution these documents are no longer needed (see 4.9.4 and 5.5.12).
The sponsor and the investigator/institution should sign the protocol, or an alternative
document, to confirm this agreement.

5.7

Allocation of Responsibilities

Prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related duties
and functions.
5.8

Compensation to Subjects and Investigators

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 frommalpractice and/or negligence.

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Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

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
should comply with applicable regulatory requirement(s).

5.9Financing

The financial aspects of the trial should be documented in an agreement between the sponsor andthe 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 requiredby the applicable regulatory requirement(s)) should submit any required application(s) to theappropriate authority(ies) for review, acceptance, and/or permission (as required by theapplicable 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/favourable opinion and, if requested by the sponsor,
a current copy of protocol, written informed consent form(s) and any other written
information to be provided to subjects, subject recruiting procedures, and documents
related to payments and compensation available to the subjects, and any otherdocuments that the IRB/IEC may have requested.
5.11.2 If the IRB/IEC conditions its approval/favourable opinion upon change(s) in any aspectof the trial, such as modification(s) of the protocol, written informed consent form andany other written information to be provided to subjects, and/or other procedures, thesponsor should obtain from the investigator/institution a copy of the modification(s)made and the date approval/favourable opinion was given by the IRB/IEC.
5.11.3 The sponsor should obtain from the investigator/institution documentation and dates of
any IRB/IEC reapprovals/re-evaluations with favourable opinion, and of any withdrawals
or suspensions of approval/favourable opinion.
5.12

Information on Investigational Product(s)5.12.1 When planning trials, the sponsor should ensure that sufficient safety and efficacy datafrom 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.
5.12.2 The sponsor should update the Investigator's Brochure as significant new information
becomes available (see 7. Investigator's Brochure).

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Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

5.13

Manufacturing, Packaging, Labelling, 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 ofdevelopment of the product(s), is manufactured in accordance with any applicable GMP,
and is coded and labelled in a manner that protects the blinding, if applicable. In addition,
the labelling should comply with applicable regulatory requirement(s).
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 andunacceptable deterioration during transport and storage.
5.13.4 In blinded trials, the coding system for the investigational product(s) should include amechanism 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 studiesof the formulated product(s) (e.g., stability, dissolution rate, bioavailability) needed toassess 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 theinvestigational 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/favourable
opinion from IRB/IEC and regulatory authority(ies)).
5.14.3 The sponsor should ensure that written procedures include instructions that theinvestigator/institution should follow for the handling and storage of investigational
product(s) for the trial and documentation thereof. The procedures should addressadequate and safe receipt, handling, storage, dispensing, retrieval of unused product fromsubjects, 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)).
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, anddestruction of the investigational product(s) (see 8. Essential Documents for the
Conduct of a Clinical Trial).

27

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice(c) Maintain a system for retrieving investigational products and documenting thisretrieval (e.g., for deficient product recall, reclaim after trial completion, expired
product reclaim).
(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 ofuse.
(b) Maintain sufficient quantities of the investigational product(s) used in the trials toreconfirm specifications, should this become necessary, and maintain records ofbatch 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 Access5.15.1 The sponsor should ensure that it is specified in the protocol or other written agreementthat the investigator(s)/institution(s) provide direct access to source data/documents fortrial-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, andregulatory 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 theregulatory authority(ies) of findings that could affect adversely the safety of subjects,
impact the conduct of the trial, or alter the IRB/IEC's approval/favourable opinion tocontinue the trial.
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) andwith 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).

28Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

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), theprotocol, written informed consent form and any other written information to beprovided 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 theextent 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 isa need for on-site monitoring, before, during, and after the trial; however in exceptional
circumstances the sponsor may determine that central monitoring in conjunction withprocedures such as investigators’ training and meetings, and extensive written guidance
can assure appropriate conduct of the trial in accordance with GCP. Statisticallycontrolled 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 monitoringclinical trials. The flexibility in the extent and nature of monitoring described in thissection is intended to permit varied approaches that improve the effectiveness andefficiency 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 themonitoring 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 atimely manner, supported by appropriately qualified and trained persons (e.g., data
managers, biostatisticians).

29

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical PracticeCentralized monitoring processes provide additional monitoring capabilities that cancomplement 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 andacross sites.
(c) evaluate for systematic or significant errors in data collection and reporting at a siteor 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 trial
is conducted and documented properly by carrying out the following activities whenrelevant 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 4.1,
4.2, 5.6) and remain adequate throughout the trial period, that facilities, including
laboratories, equipment, and staff, are adequate to safely and properly conduct thetrial 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 trialsites 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 withthe 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).
30Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice(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 thespecified trial functions, in accordance with the protocol and any other writtenagreement between the sponsor and the investigator/institution, and have notdelegated these functions to unauthorized individuals.
(i) Verifying that the investigator is enroling 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 andother 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 areconsistent with the source documents.

(ii)

Any dose and/or therapy modifications are well documented for each of thetrial subjects.

(iii) Adverse events, concomitant medications and intercurrent illnesses arereported in accordance with the protocol on the CRFs.
(iv) Visits that the subjects fail to make, tests that are not conducted, andexaminations 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 initialled by the investigator or by a member ofthe investigator's trial staff who is authorized to initial CRF changes for theinvestigator. This authorization should be documented.
(o) Determining whether all adverse events (AEs) are appropriately reported within thetime periods required by GCP, the protocol, the IRB/IEC, the sponsor, and theapplicable regulatory requirement(s).
(p) Determining whether the investigator is maintaining the essential documents (see 8.
Essential Documents for the Conduct of a Clinical Trial).
(q) Communicating deviations from the protocol, SOPs, GCP, and the applicableregulatory requirements to the investigator and taking appropriate action designed toprevent 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.

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Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

5.18.6 Monitoring Report(a) The monitor should submit a written report to the sponsor after each trial-site visit ortrial-related communication.
(b) Reports should include the date, site, name of the monitor, and name of theinvestigator 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 securecompliance.
(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 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 themonitoring plan. Reporting of centralized monitoring activities should be regularand 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 humansubject protection and data integrity risks of the trial. The plan should describe themonitoring strategy, the monitoring responsibilities of all the parties involved, thevarious 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 andprocedures.

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 andcompliance 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.

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Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

5.19.3 Auditing Procedures(a) The sponsor should ensure that the auditing of clinical trials/systems is conducted inaccordance with the sponsor's written procedures on what to audit, how to audit, thefrequency 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 theimportance of the trial to submissions to regulatory authorities, the number ofsubjects 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.
(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

Noncompliance5.20.1 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 affecthuman 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 theregulatory authority(ies).
5.21

Premature Termination or Suspension of a Trial

If a trial is prematurely terminated or suspended, the sponsor should promptly inform theinvestigators/institutions, and the regulatory authority(ies) of the termination or suspension andthe 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 theinvestigator/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 theclinical trial reports are prepared and provided to the regulatory agency(ies) as required by theapplicable regulatory requirement(s). The sponsor should also ensure that the clinical trial reports
in marketing applications meet the standards of the ICH Guideline for Structure and Content of33

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical PracticeClinical Study Reports. (NOTE: The ICH Guideline for Structure and Content of Clinical Study
Reports specifies that abbreviated study reports may be acceptable in certain cases.)
5.23

Multicentre Trials

For multicentre trials, the sponsor should ensure that:
5.23.1 All investigators conduct the trial in strict compliance with the protocol agreed to by thesponsor and, if required, by the regulatory authority(ies), and given approval/favourable
opinion by the IRB/IEC.
5.23.2 The CRFs are designed to capture the required data at all multicentre trial sites. For thoseinvestigators 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 auniform 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.
6.1

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, andthe address and telephone number(s) of the trial site(s).

6.1.6Name, 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 (ifother than investigator).

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Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

6.1.7

Name(s) and address(es) of the clinical laboratory(ies) and other medical and/or technicaldepartment(s) and/or institutions involved in the trial.

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 clinicalsignificance 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 theapplicable 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 bemeasured during the trial.

6.4.2

A description of the type/design of trial to be conducted (e.g., double-blind, placebocontrolled, parallel design) and a schematic diagram of trial design, procedures andstages.

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 theinvestigational product(s). Also include a description of the dosage form, packaging, andlabelling of the investigational product(s).

6.4.5

The expected duration of subject participation, and a description of the sequence andduration of all trial periods, including follow-up, if any.

6.4.6

A description of the "stopping rules" or "discontinuation criteria" for individual subjects,
parts of trial and entire trial.
35

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

6.4.7

Accountability procedures for the investigational product(s), including the placebo(s) andcomparator(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), thedose(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 producttreatment/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 analysing of efficacy parameters.

6.8

Assessment of Safety

6.8.1

Specification of safety parameters.

6.8.2

The methods and timing for assessing, recording, and analysing safety parameters.

6.8.3

Procedures for eliciting reports of and for recording and reporting adverse event andintercurrent illnesses.

6.8.4

The type and duration of the follow-up of subjects after adverse events.
36

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

6.9

Statistics

6.9.1

A description of the statistical methods to be employed, including timing of any plannedinterim analysis(ses).

6.9.2

The number of subjects planned to be enrolled. In multicentre trials, the numbers ofenrolled subjects projected for each trial site should be specified. Reason for choice ofsample size, including reflections on (or calculations of) the power of the trial andclinical 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 (anydeviation(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 theinvestigator(s)/institution(s) will permit trial-related monitoring, audits, IRB/IEC review, andregulatory inspection(s), providing direct access to source data/documents.
6.11

Quality Control and Quality Assurance

6.12

EthicsDescription of ethical considerations relating to the trial.
6.13

Data Handling and Record Keeping

6.14

Financing and Insurance

Financing and insurance if not addressed in a separate agreement.
6.15

Publication Policy

Publication policy, if not addressed in a separate agreement.
6.16

Supplements(NOTE: Since the protocol and the clinical trial/study report are closely related, further relevant
information can be found in the ICH Guideline for Structure and Content of Clinical Study
Reports.)

37

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice7.

INVESTIGATOR’S BROCHURE

7.1

Introduction

The Investigator's Brochure (IB) is a compilation of the clinical and nonclinical data on theinvestigational 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 tofacilitate their understanding of the rationale for, and their compliance with, many key featuresof 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 thestudy subjects during the course of the clinical trial. The information should be presented in a
concise, simple, objective, balanced, and non-promotional form that enables a clinician, or
potential investigator, to understand it and make his/her own unbiased risk-benefit assessment of
the appropriateness of the proposed trial. For this reason, a medically qualified person should
generally participate in the editing of an IB, but the contents of the IB should be approved by thedisciplines that generated the described data.
This guideline delineates the minimum information that should be included in an IB andprovides 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 theinvestigational product is marketed and its pharmacology is widely understood by medical
practitioners, an extensive IB may not be necessary. Where permitted by regulatory authorities, abasic 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 amarketed 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 asnecessary in compliance with a sponsor's written procedures. More frequent revision may beappropriate depending on the stage of development and the generation of relevant new
information. However, in accordance with Good Clinical Practice, relevant new information may
be so important that it should be communicated to the investigators, and possibly to theInstitutional 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 theinvestigator(s) and the investigators are responsible for providing the up-to-date IB to the
responsible IRBs/IECs. In the case of an investigator sponsored trial, the sponsor-investigatorshould determine whether a brochure is available from the commercial manufacturer. If theinvestigational product is provided by the sponsor-investigator, then he or she should provide thenecessary information to the trial personnel. In cases where preparation of a formal IB is
impractical, the sponsor-investigator should provide, as a substitute, an expanded backgroundinformation section in the trial protocol that contains the minimum current information describedin this guideline.
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 legallypermissible and desired by the sponsor), and the release date. It is also suggested that an38

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practiceedition number, and a reference to the number and date of the edition it supersedes, be
provided. An example is given in Appendix 1.
7.2.2

Confidentiality Statement
The sponsor may wish to include a statement instructing the investigator/recipients totreat the IB as a confidential document for the sole information and use of theinvestigator'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 thesignificant physical, chemical, pharmaceutical, pharmacological, toxicological,
pharmacokinetic, metabolic, and clinical information available that is relevant to thestage of clinical development of the investigational product.

7.3.3

Introduction
A brief introductory statement should be provided that contains the chemical name (andgeneric 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 tobe 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 therelevant physical, chemical, and pharmaceutical properties.
To permit appropriate safety measures to be taken in the course of the trial, a descriptionof 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, andinvestigational product metabolism studies should be provided in summary form. Thissummary should address the methodology used, the results, and a discussion of the39Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practicerelevance of the findings to the investigated therapeutic and the possible unfavourable
and unintended effects in humans.
The information provided may include the following, as appropriate, if known/available:










Species tested
Number and sex of animals in each group
Unit dose (e.g., milligram/kilogram (mg/kg))
Dose interval
Route of administration
Duration of dosing
Information on systemic distribution
Duration of post-exposure follow-up
Results, including the following aspects: Nature and frequency of pharmacological or toxic effects
 Severity or intensity of pharmacological or toxic effects
 Time to onset of effects
 Reversibility of effects
 Duration of effects
 Dose response
Tabular format/listings should be used whenever possible to enhance the clarity of thepresentation.
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/tissuelevels rather than on a mg/kg basis.

(a) Nonclinical Pharmacology
A summary of the pharmacological aspects of the investigational product and, whereappropriate, its significant metabolites studied in animals, should be included. Such asummary 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 theinvestigational product in all species studied should be given. The discussion of thefindings should address the absorption and the local and systemic bioavailability of theinvestigational product and its metabolites, and their relationship to the pharmacologicaland toxicological findings in animal species.
(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:40Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice Single dose
 Repeated dose
 Carcinogenicity
 Special studies (e.g., irritancy and sensitisation)
 Reproductive toxicity
 Genotoxicity (mutagenicity)
7.3.6

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 withinclinical 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 ofsafety 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. Importantdifferences 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 andwith 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 orapproved. Any significant information arising from the marketed use should besummarised (e.g., formulations, dosages, routes of administration, and adverse productreactions). The IB should also identify all the countries where the investigational product41

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

did not receive approval/registration for marketing or was withdrawn frommarketing/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, andshould summarise the information from various sources on different aspects of theinvestigational product(s), wherever possible. In this way, the investigator can beprovided with the most informative interpretation of the available data and with anassessment 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 inclinical 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, andprecautions that may be needed for a clinical trial. This understanding should be based on
the available physical, chemical, pharmaceutical, pharmacological, toxicological, andclinical information on the investigational product(s). Guidance should also be provided tothe clinical investigator on the recognition and treatment of possible overdose and adverse
drug reactions that is based on previous human experience and on the pharmacology of theinvestigational product.

42

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

7.4

APPENDIX 1:

TITLE PAGE (Example)
SPONSOR'S NAME
Product:
Research Number:Name(s):Chemical, Generic (if approved)
Trade Name(s) (if legally permissible and desired by the sponsor)
INVESTIGATOR'S BROCHURE

Edition Number:
Release Date:

Replaces Previous Edition Number:
Date:

43

Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice

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)

44

Integrated Addendum to E6(R1): Guideline for Good Clinical Practice8.

ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL

8.1

Introduction

Essential Documents are those documents which individually and collectively permit evaluation of the conduct of a trial and the quality of thedata produced. These documents serve to demonstrate the compliance of the investigator, sponsor and monitor with the standards of Good
Clinical Practice and with all applicable regulatory requirements.
Essential Documents also serve a number of other important purposes. Filing essential documents at the investigator/institution and sponsor sites
in a timely manner can greatly assist in the successful management of a trial by the investigator, sponsor and monitor. These documents are also
the ones which are usually audited by the sponsor's independent audit function and inspected by the regulatory authority(ies) as part of theprocess to confirm the validity of the trial conduct and the integrity of data collected.
The minimum list of essential documents which has been developed follows. The various documents are grouped in three sections according to
the stage of the trial during which they will normally be generated: 1) before the clinical phase of the trial commences, 2) during the clinicalconduct of the trial, and 3) after completion or termination of the trial. A description is given of the purpose of each document, and whether itshould be filed in either the investigator/institution or sponsor files, or both. It is acceptable to combine some of the documents, provided theindividual 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 allnecessary documents are in the appropriate files.
Any or all of the documents addressed in this guideline may be subject to, and should be available for, audit by the sponsor’s auditor andinspection 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 theimportance and relevance of the specific documents to the trial.

45

Integrated Addendum to E6(R1): Guideline for Good Clinical PracticeThe 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

PurposeLocated in Files ofInvestigator/
SponsorInstitution

8.2.1

INVESTIGATOR’S BROCHURE

To document that relevant and current scientificinformation about the investigational product has
been provided to the investigator

X

X

8.2.2

SIGNED PROTOCOL AND AMENDMENTS,
IF ANY, AND SAMPLE CASE REPORTFORM (CRF)

To document investigator and sponsor agreement
to the protocol/amendment(s) and CRF

X

X

8.2.3

INFORMATION GIVEN TO TRIALSUBJECT

X

X

X

X

- INFORMED CONSENT FORM
(including all applicable translations)

To document the informed consent- ANY OTHER WRITTEN INFORMATION

To document that subjects will be given
appropriate written information (content andwording) to support their ability to give fully
informed consent

46Integrated Addendum to E6(R1): Guideline for Good Clinical Practice

Title of Document

PurposeLocated in Files ofInvestigator/
SponsorInstitution- ADVERTISEMENT FOR SUBJECTRECRUITMENT (if used)

To document that recruitment measures areappropriate and not coercive

X

8.2.4

FINANCIAL ASPECTS OF THE TRIAL

To document the financial agreement between theinvestigator/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 BETWEENINVOLVED PARTIES, e.g.:- investigator/institution and sponsor- investigator/institution and CRO

To document agreements
X
X

X
X

-

(where required)sponsor and CRO
investigator/institution and authority(ies)(where required)

X

47

X
X

Integrated Addendum to E6(R1): Guideline for Good Clinical Practice

8.2.7

Title of Document

PurposeDATED, DOCUMENTED
APPROVAL/FAVOURABLE OPINION OF
INSTITUTIONAL REVIEW BOARD (IRB)/INDEPENDENT ETHICS COMMITTEE(IEC) OF THE FOLLOWING:- protocol and any amendments- CRF (if applicable)- informed consent form(s)- any other written information to be provided
to the subject(s)- advertisement for subject recruitment(if used)- subject compensation (if any)
- any other documents given approval/
favourable opinion

To document that the trial has been subject to
IRB/IEC review and given approval/favourable
opinion. To identify the version number and dateof the document(s)48Located in Files ofInvestigator/
SponsorInstitution
X

X

Integrated Addendum to E6(R1): Guideline for Good Clinical Practice

Title of Document

PurposeLocated in Files ofInvestigator/
SponsorInstitution

INSTITUTIONAL REVIEWBOARD/INDEPENDENT ETHICSCOMMITTEE COMPOSITION

To document that the IRB/IEC is constituted inagreement with GCP

X

REGULATORY AUTHORITY(IES)
AUTHORISATION/APPROVAL/NOTIFICATION OF PROTOCOL(where required)

To document appropriate
authorisation/approval/notification by theregulatory authority(ies) has been obtained prior toinitiation of the trial in compliance with theapplicable regulatory requirement(s)XX(whererequired)(whererequired)

8.2.10CURRICULUM VITAE AND/OR OTHER
RELEVANT DOCUMENTS EVIDENCINGQUALIFICATIONS OF INVESTIGATOR(S)AND SUB-INVESTIGATOR(S)To document qualifications and eligibility to
conduct trial and/or provide medical supervision ofsubjects

XX

8.2.11NORMAL VALUE(S)/RANGE(S) FOR
MEDICAL/ LABORATORY/TECHNICALPROCEDURE(S) AND/OR TEST(S)INCLUDED IN THE PROTOCOL

To document normal values and/or ranges of the
tests

X

X

8.2.8

8.2.9

49

X
(whererequired)Integrated Addendum to E6(R1): Guideline for Good Clinical Practice

Title of Document

PurposeLocated in Files ofInvestigator/
SponsorInstitution

MEDICAL/LABORATORY/TECHNICALPROCEDURES /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

8.2.13

SAMPLE OF LABEL(S) ATTACHED TO
INVESTIGATIONAL PRODUCTCONTAINER(S)To document compliance with applicable labelling
regulations and appropriateness of instructions
provided to the subjects

8.2.14

To document instructions needed to ensure proper
INSTRUCTIONS FOR HANDLING OF
storage, packaging, dispensing and disposition of
INVESTIGATIONAL PRODUCT(S) AND
investigational products and trial-related materials
TRIAL-RELATED MATERIALS(if not included in protocol or Investigator’sBrochure)XX

8.2.15

SHIPPING RECORDS FORINVESTIGATIONAL PRODUCT(S) AND
TRIAL-RELATED MATERIALS

To document shipment dates, batch numbers andmethod of shipment of investigational product(s)and trial-related materials. Allows tracking ofproduct batch, review of shipping conditions, andaccountability

XX

8.2.12

50

X

X(whererequired)XIntegrated Addendum to E6(R1): Guideline for Good Clinical Practice

Title of Document

Purpose8.2.16

To document identity, purity, and strength of
CERTIFICATE(S) OF ANALYSIS OFINVESTIGATIONAL PRODUCT(S) SHIPPED investigational product(s) to be used in the trial

8.2.17

DECODING PROCEDURES FOR BLINDEDTRIALS

To document how, in case of an emergency,
identity of blinded investigational product can berevealed without breaking the blind for theremaining subjects' treatment

51

Located in Files ofInvestigator/
SponsorInstitution
X

X

X(third party if
applicable)

Integrated Addendum to E6(R1): Guideline for Good Clinical Practice

Title of Document

8.2.18MASTER RANDOMISATION LIST

PurposeLocated in Files ofInvestigator/
SponsorInstitution

To document method for randomisation 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 MONITORINGREPORT

To document that trial procedures were reviewed
with the investigator and the investigator’s trial
staff ( may be combined with 8.2.19)

52

X(third party if
applicable)

X
X

X

Integrated Addendum to E6(R1): Guideline for Good Clinical Practice8.3
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

PurposeLocated in Files ofInvestigator/
Institution

Sponsor

8.3.1

INVESTIGATOR’S BROCHURE UPDATESTo document that investigator is informed in atimely manner of relevant information as it
becomes available

X

X

8.3.2

ANY REVISION TO:- protocol/amendment(s) and CRF- informed consent form
- any other written information provided tosubjects- advertisement for subject recruitment(if used)

To document revisions of these trial related
documents that take effect during trial

X

X

53

Integrated Addendum to E6(R1): Guideline for Good Clinical Practice

Title of Document

8.3.3

DATED, DOCUMENTED
APPROVAL/FAVOURABLE OPINION OF
INSTITUTIONAL REVIEW BOARD (IRB)/INDEPENDENT ETHICS COMMITTEE(IEC) OF THE FOLLOWING:--

PurposeTo document that the amendment(s) and/or
revision(s) have been subject to IRB/IEC review
and were given approval/favourable opinion. To
identify the version number and date of the
document(s).

Located in Files ofInvestigator/
Institution

Sponsor

X

X

X(whererequired)

X

X

X

protocol amendment(s)revision(s) of:- informed consent form
- any other written information to beprovided to the subject- advertisement for subject recruitment(if used)
any other documents given
approval/favourable opinion
continuing review of trial (where required)

8.3.4

REGULATORY AUTHORITY(IES)
AUTHORISATIONS/APPROVALS/NOTIFICATIONS WHERE REQUIRED FOR:
- protocol amendment(s) and other documents

To document compliance with applicableregulatory requirements

8.3.5

CURRICULUM VITAE FOR NEW
INVESTIGATOR(S) AND/OR SUBINVESTIGATOR(S)(see 8.2.10)

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Title of Document

Purpose

8.3.6

UPDATES TO NORMALVALUE(S)/RANGE(S) FOR MEDICAL/LABORATORY/ TECHNICALPROCEDURE(S)/TEST(S) INCLUDED IN
THE PROTOCOL

To document normal values and ranges that arerevised during the trial (see 8.2.11)

8.3.7

UPDATES OF MEDICAL/LABORATORY/TECHNICAL PROCEDURES/TESTS

To document that tests remain adequate throughout
the trial period (see 8.2.12)-

certification or
accreditation or
established quality control and/or external
quality assessment orother validation (where required)

Located in Files ofInvestigator/
Institution

Sponsor

X

X

X(whererequired)

X

X

X

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 INVESTIGATIONALPRODUCTS(see 8.2.16)

X

8.3.10MONITORING VISIT REPORTS

To document site visits by, and findings of, themonitorX

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Title of Document

8.3.11RELEVANT COMMUNICATIONS OTHER
THAN SITE VISITS-

letters
meeting notes
notes of telephone calls

PurposeLocated in Files ofInvestigator/
Institution

SponsorTo document any agreements or significant
discussions regarding trial administration, protocol
violations, trial conduct, adverse event (AE)reportingXX

8.3.12SIGNED INFORMED CONSENT FORMS

To document that consent is obtained inaccordance 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 andsubstantiate integrity of trial data collected. To
include original documents related to the trial, to
medical treatment, and history of subject

X

8.3.14SIGNED, DATED AND COMPLETEDCASE REPORT FORMS (CRF)

To document that the investigator or authorised
member of the investigator’s staff confirms theobservations recordedX(copy)

X(original)

8.3.15

DOCUMENTATION OF CRF
CORRECTIONS

To document all changes/additions or corrections
made to CRF after initial data were recordedX(copy)

X(original)

8.3.16

NOTIFICATION BY ORIGINATINGINVESTIGATOR TO SPONSOR OF
SERIOUS ADVERSE EVENTS AND
RELATED REPORTS

Notification by originating investigator to sponsorof serious adverse events and related reports inaccordance with 4.11

X

X

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Title of Document

PurposeLocated in Files ofInvestigator/
Institution

Sponsor

8.3.17

NOTIFICATION BY SPONSOR AND/ORINVESTIGATOR, WHERE APPLICABLE,
TO REGULATORY AUTHORITY(IES) AND
IRB(S)/IEC(S) OF UNEXPECTED SERIOUS
ADVERSE DRUG REACTIONS AND OFOTHER SAFETY INFORMATION

Notification by sponsor and/or investigator, whereapplicable, to regulatory authorities andIRB(s)/IEC(s) of unexpected serious adverse drug
reactions in accordance with 5.17 and 4.11.1 andof other safety information in accordance with
5.16.2 and 4.11.2

X(whererequired)X

8.3.18NOTIFICATION BY SPONSOR TO
INVESTIGATORS OF SAFETYINFORMATION

Notification by sponsor to investigators of safety
information in accordance with 5.16.2

XX

8.3.19INTERIM 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) inaccordance with 5.17.3

X

X(whererequired)

8.3.20SUBJECT SCREENING LOG

To document identification of subjects whoentered pre-trial screening

X

X(whererequired)

8.3.21SUBJECT IDENTIFICATION CODE LIST

To document that investigator/institution keeps a
confidential list of names of all subjects allocatedto trial numbers on enrolling in the trial. Allows
investigator/institution to reveal identity of any
subject

X

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Title of Document

PurposeLocated in Files ofInvestigator/
Institution

Sponsor

8.3.22SUBJECT ENROLMENT LOG

To document chronological enrolment of subjects
by trial numberX

8.3.23INVESTIGATIONAL PRODUCTS
ACCOUNTABILITY AT THE SITE

To document that investigational product(s) havebeen used according to the protocol

XX

8.3.24

SIGNATURE SHEETTo document signatures and initials of all persons
authorised to make entries and/or corrections on
CRFs

X

X

8.3.25

RECORD OF RETAINED BODY FLUIDS/
TISSUE SAMPLES (IF ANY)

To document location and identification ofretained samples if assays need to be repeated

X

X

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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 thefollowing
Title of Document

PurposeLocated in Files ofInvestigator/
SponsorInstitution

8.4.1

INVESTIGATIONAL PRODUCT(S)ACCOUNTABILITY AT SITE

To document that the investigational product(s)have been used according to the protocol. To
documents the final accounting of investigational
product(s) received at the site, dispensed tosubjects, returned by the subjects, and returned tosponsor

8.4.2

DOCUMENTATION OF
INVESTIGATIONAL PRODUCTDESTRUCTION

To document destruction of unused investigationalX
products by sponsor or at site
(if destroyed at
site)

8.4.3

COMPLETED SUBJECT IDENTIFICATIONCODE 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 MONITORINGREPORT

To document that all activities required for trial
close-out are completed, and copies of essential
documents are held in the appropriate files

X

59

X

X

X

X

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Title of Document

PurposeLocated in Files ofInvestigator/
SponsorInstitution

Returned to sponsor to document any decodingthat may have occurred

8.4.6

TREATMENT ALLOCATION AND
DECODING DOCUMENTATION

8.4.7

To document completion of the trial
FINAL REPORT BY INVESTIGATOR TO
IRB/IEC WHERE REQUIRED, AND WHERE
APPLICABLE, TO THE REGULATORYAUTHORITY(IES)

8.4.8

CLINICAL STUDY REPORT

To document results and interpretation of trial

60

X
X

X
(if applicable)

X