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ICH
Harmonised
Tripartite
Guideline for
Good Clinical
Practice

Pharmacia
&Upjohn
This booklet has been provided by Global Quality Assurance

BROOKWOOD MEDICAL PUBLICATIONS
!

Contents

INTRODUCTION

I. GLOSSARY

I

2. THE PRINCIPLES OF ICH
GCP
10

.1
3. INSTITUTIONAL REVIEW
BOARD I INDEPENDENT
ETHICS COMMITTEE
(IRB/IEC)
11
3.1 Responsibilities
11
3.2 Composition, Functions and
Operations
12
3.3 Procedures
13
3.4 Records
14
4. INVESTIGATOR
IS
4.1 Investigator’s Qualifications
and Agreements
15
4.2 Adequate Resources .. 15
4.3 Medical Care of Trial
Subjects
15
4.4 Communication with
IRB/IEC
16
4.5 Compliance with
Protocol
16
4.6 Investigational
Product(s)
17
4.7 Randomization Procedures
and Unblinding
18
4.8 Informed Consent of Trial
Subjects
18
4.9 Records and Reports .. 22
4.10 Progress Reports
23
4.11 Safety Reporting
23
4.12 Premature Termination or
Suspension of a Trial .. 23
4.13 Final Report(s) by
Investigator
24

5. SPONSOR
25
5.1 Quality Assurance and
Quality Control
25
5.2 Contract Research
Organization (CRO).... 25
5.3 Medical Expertise
25
5.4 Trial Design
25
5.5 Trial Management, Data
Handling, and Record
Keeping
26
5.6 Investigator Selection.. 27
5.7 Allocation of Duties and
Functions
28
5.8 Compensation to Subjects
and Investigators
28
28
5.9 Financing
5.10 Notification/Submission
to Regulatory
Authority(ies)
28
5.11 Confirmation of Review by
IRB/IEC
29
5.12 Information on Invest­
igational Product(s)
29
5.13 Manufacturing, Packaging,
Labelling, and Coding
Investigational
Product(s) ................. 29
5.14 Supplying and Handling
Investigational
Product(s)
30
5.15 Record Access
31
5.16 Safety Information
31
5.17 Adverse Drug Reaction
Reporting
31
5.18 Monitoring
32
5.18.1 Purpose
32
5.18.2 Selection and Qualifi­
cations of Monitors
32
5.18.3 Extent and Nature of
Monitoring
32

i
'•

I CH Guideline for GCP

5.18.4 Monitor’s
32
Responsibilities....
5.18.5 Monitoring
34
Procedures .........
5.18.6 Monitoring
Report....................... 35
5.19 Audit ......................... 35
5.19.1 Purpose........... 35
5.19.2 Selection and Qualifi­
cation of Auditors..... 35
5.19.3 Auditing
Procedures ............... 35
5.20 Noncompliance......... 36
5.21 Premature Termination or
Suspension of a Trial .. 36
5.22 Clinical Trial/Study
36
Reports..............
36
5.23 Multicentre Trials

6. CLINICAL TRIAL PROTO­
COL AND PROTOCOL
AMENDMENT(S).... 38
6.1 General Information ... 38
6.2 Background
38
Information..............
6.3 Trial Objectives and
39
Purpose ................ .
39
6.4 Trial Design ...........

6.5

41

7. INVESTIGATOR’S
BROCHURE ................... 42
7.1 Introduction .............. 42
7.2 General Considerations 43
43
7.2.1 Title Page ......
7.2.2 Confidentiality
43
Statement...............
7.3 Contents of the
Investigator’s Brochure 43
7.3.1 Table of Contents 43
7.3.2 Summary .......... 43
7.3.3 Introduction ..... 43
7.3.4 Physical, Chemical,
and Pharmaceutical
Properties and
Formulation.............. 44
7.3.5 Nonclinical Studies 44
7.3.6 Effects in Humans 45
7.3.7 Summary of Data and
Guidance for the
46
Investigator
47
7.4 Appendix I
47
7.5 Appendix 2

Selection and Withdrawal

of Subjects................. 39
6.6 Treatment of Subjects .. 40
6.7 Assessment of Efficacy.. 40
6.8 Assessment of Safety... 40
6.9 Statistics..................... 40
6.10 Direct Access to Source
Data/Documents....... 41
6.11 ’Quality Control and Quality
Assurance................. 41
6.12 Ethics......................... 41
6.13 Data Handling and Record

ii

Keeping.......

6.14 Financing andInsurance 41
6.15 Publication Policy ...... 41
6.16 Supplements.............. 41

8. ESSENTIAL DOCUMENTS
FOR THE CONDUCT OF A
CLINICAL TRIAL... 48
8.1 Introduction .............. 48
8.2 Before the Clinical Phase of
the Trial Commences ... 49
8.3 During the Clinical Conduct
53
of the Trial..............
8.4 After Completion or
Termination of
59
the Trial..................

Glossary

I. GLOSSARY

INTRODUCTION
Good Clinical Practice (GCP) is an
international ethical and scientific
quality standard for designing,
conducting, recording and reporting
trials that involve the participation
of human subjects. Compliance with
this standard provides public assur­
ance that the rights, safety and well­
being of trial subjects are protected,
consistent with the principles that
have their origin in the Declaration
of Helsinki, and that the clinical trial
data are credible.
The objective of this ICH GCP
Guideline is to provide a unified
standard for the European Union
(EU), Japan and the United States to
facilitate the mutual acceptance of
clinical data by the regulatory
authorities in these jurisdictions.
The guideline was developed
with consideration of the current
good clinical practices of the
European Union, Japan, and the
United States, as well as those of
Australia, Canada, the Nordic
countries and the World Health
Organization (WHO).
This guideline should be
followed when generating clinical
trial data that are intended to be
submitted to regulatory authorities.
The principles established in this
guideline may also be applied to
other clinical investigations that may
have an impact on the safety and
well-being of human subjects.

1.1 Adverse Drug Reaction

(ADR)
In the pre-approval clinical experi­

ence with a new medicinal product

or its new usages, particularly as the
therapeutic dose(s) may not be

established: all noxious and unin­
tended responses to a medicinal

product related to any dose should
be considered adverse drug reac­

tions. The phrase responses to a

medicinal product means that a

causal relationship between a medic­
inal product and an adverse event is

at least a reasonable possibility, ie.
the relationship cannot be ruled out.
Regarding marketed medicinal pro­

ducts: 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 modifica­

tion 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 sub­
ject administered a pharmaceutical

product and which does not neces­

sarily have a causal relationship with
this treatment. An adverse event

(AE) can therefore be any unfavour­
able and unintended sign (including

i

I CH Guideline for GCP

an abnormal laboratory finding),
symptom, or disease temporally
associated with the use of a medi­
cinal (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) address­
ing 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 con­
straints set forth by the IRB, the
institution, Good Clinical Practice
(GCP), and the applicable regulatory
requirements.

1.6 Audit
A systematic and independent exam­
ination 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,

2

sponsor’s standard operating proce­
dures (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 spon­
sor’s auditor of the results of the
audit.
1.9 Audit Trail
Documentation that allows recon­
struction 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 dou­
ble-blinding usually refers to the sub­
jects), investigator(s), monitor, and,
in some cases, data analyst(s) being
unaware of the treatment assignments).

1. 11 Case Report Form (CRF)
A printed, optical, or electronic doc­
ument designed to record all of the
protocol required information to be
reported to the sponsor on each

trial subject.
1.12 Clinical Trial/Study
Any investigation in human subjects
intended to discover or verify the
clinical, pharmacological and/or other

Glossary

pharmacodynamic effects of an inves­
tigational product(s), and/or to identi­
fy any adverse reactions to an investi­
gational product(s), and/or to study
absorption, distribution, metabolism,
and excretion of an investigational
product(s) with the object of ascer­
taining its safety and/or efficacy. The
terms clinical trial and clinical study
are synonymous.

1.13 Clinical Trial/Study
Report
A written description of a trial/study
of any therapeutic, prophylactic, or
diagnostic agent conducted in human
subjects, in which the clinical and
statistical description, presentations,
and analyses are fully integrated into
a single report (see the ICH
Guideline for Structure and Content
of Clinical Study Reports).
1.14 Comparator (Product)
An investigational or marketed prod­
uct (ie. active control), or placebo,
used as a reference in a clinical trial.

1.17 Contract
A written, dated, and signed agree­
ment between two or more involved

parties that sets out any arrangements
on delegation and distribution of
tasks and obligations and, if appropri­
ate, 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 respon­
sibility for the coordination of inves­
tigators at different centres partici­
pating in a multicentre trial.
1.20 Contract Research
Organization (CRO)
A person or an organization (com­
mercial, academic, or other) con­
tracted by the sponsor to perform
one or more of a sponsor’s trialrelated duties and functions.

1.15 Compliance (in relation
to trials)
Adherence to all the trial-related
requirements, Good Clinical Practice
(GCP) requirements, and the appli­
cable 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.

1.21 Direct Access
Permission to examine, analyze, ver­
ify, and reproduce any records and
reports that are important to evalua­
tion 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 with­
in the constraints of the applicable
regulatory requirement(s) to main-

3

ICH Guideline for GCP

tain the confidentiality of subjects’
identities and sponsor’s proprietary
information.
1.22 Documentation
All records, in any form (including,
but not limited to, written, electron­
ic, magnetic, and optical records, and
$cans, x-rays, and electrocardio­
grams) that describe or record the
methods, conduct, and/or results of
a trial, the factors affecting a trial,
and the actions taken.
1.23 Essential Documents
Documents which individually and
collectively permit evaluation of the
conduct of a study and the quality of
the data produced (see 8. Essential
Documents for the Conduct of a
Clinical Trial).
1.24 Good Clinical Practice
(GCP)
A standard for the design, conduct,
performance, monitoring, auditing,
recording, analyses, and reporting of
clinical trials that provides assurance
that the data and reported results
are credible and accurate, and that
the rights, integrity, and confidentiali­
ty of trial subjects are protected.

1.25 Independent DataMonitoring Committee
(IDMC) (Data and Safety
Monitoring Board, Monitoring
Committee, Data Monitoring
Committee)
An independent data-monitoring

4

committee that may be established
by the sponsor to assess at intervals
the progress of a clinical trial, the
safety data, and the critical efficacy
endpoints, and to recommend to the
sponsor whether to continue, modi­
fy, or stop a trial.
1.26 Impartial Witness
A person, who is independent of the
trial, who cannot be unfairly influ­
enced by people involved with the
trial, who attends the informed con­
sent process if the subject or the
subject’s legally acceptable represen­
tative cannot read, and who reads
the informed consent form and any
other written information supplied
to the subject.

1.27 Independent Ethics
Committee (IEC)
An independent body (a review
board or a committee, institutional,
regional, national, or supranational),
constituted of medical/scientific pro­
fessionals and non-medical/non-scientific members, whose responsibili­
ty it is to ensure the protection of
the rights, safety and well-being of
human subjects involved in a trial
and to provide public assurance of
that protection, by, among other
things, reviewing and approving/providing favourable opinion on, the
trial protocol, the suitability of the
investigator(s), facilities, and the
methods and material to be used in
obtaining and documenting informed
consent of the trial subjects.

Glossary

The legal status, composition, func­

1.31 Institutional Review

tion, operations and regulatory

Board (IRB)
An independent body constituted of

requirements

pertaining

to

Independent Ethics Committees may
differ among countries, but should

medical, scientific, and non-scientific

members, whose responsibility is to

Ethics

ensure the protection of the rights,

Committee to act in agreement with

safety and well-being of human sub­

GCP as described in this guideline.

jects involved in a trial by, among

allow

the

Independent

1.28 Informed Consent

other things, reviewing, approving,
and providing continuing review of

A process by which a subject volun­

trial protocol and amendments and

tarily confirms his or her willingness
to participate in a particular trial,

of the methods and material to be

after having been informed of all

formed consent of the trial subjects.

used in obtaining and documenting in­

aspects of the trial that are relevant

to the subject’s decision to partici­

1.32 Interim Clinical Trial/

pate. Informed consent is document­
ed by means of a written, signed and

Study Report
A report of intermediate results and

dated informed consent form.

their evaluation based on analyses

performed during the course of a

1.29 Inspection
The
act
by

trial.

a

regulatory

authority(ies) of conducting an offi­

1.33 Investigational Product

cial review of documents, facilities,

A pharmaceutical form of an active
ingredient or placebo being tested

records, and any other resources
that
are
deemed
by
the

or used as a reference in a clinical

authority(ies) to be related to the

trial, including a product with a mar­

clinical trial and that may be located

keting authorization when used or

at the site of the trial, at the spon­

assembled (formulated or packaged)

sor’s and/or contract research orga­
nization’s (CRO’s) facilities, or at
other establishments deemed

form, or when used for an
unapproved indication, or when used

appropriate by the regulatory

to gain further information about an

authority(ies).

approved use.

1.30 Institution (medical)

1.34 Investigator
A person responsible for the con­

Any public or private entity or agen­
cy or medical or dental facility where
clinical trials are conducted.

in a way different from the approved

duct of the clinical trial at a trial site.
If a trial is conducted by a team of
individuals at a trial site, the investi-

5

ICH Guideline for GCP

gator 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 investi­
gator and/or institution, where
required by the applicable regulatory
i"equirements”.
1.36 Investigator’s Brochure
A compilation of the clinical and
nondinical data on the investigational
product(s) which is relevant to the
study of the investigational
product(s) in human subjects (see
7. Investigator s Brochure).
1.37 Legally Acceptable
Representative
An individual or juridical or other
body authorized under applicable
law to consent, on behalf of a
prospective subject, to the subject’s
participation in the clinical trial.

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 Nondinical 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.

1.38 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).

1.44 Protocol
A document that describes the
objective(s), design, methodology,
statistical considerations, and organi­
zation of a trial. The protocol usually
also gives the background and ratio­
nale for the trial, but these could be
provided in other protocol refer­
enced documents. Throughout the
ICH GCP Guideline the term proto­
col refers to protocol and protocol
amendments.

1.39 Monitoring Report
A written report from the monitor
to the sponsor after each site
visit and/or other trial-related

1.45 Protocol Amendment
A written description of a change(s)
to or formal clarification of a
protocol.

6

r

Glossary

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, docu­
mented (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 qual­
ity assurance system to verify that
the requirements for quality of the
trial-related activities have been ful­

filled.
1.48 Randomization
The process of assigning trial sub­
jects to treatment or control groups
using an element of chance to deter­
mine 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 re­
ferred to as competent authorities.
1.50 Serious Adverse Event
(SAE) or Serious Adverse
Drug Reaction (Serious ADR)
Any untoward medical occurrence
that at any dose:

- results in death,
- is life-threatening,
- requires inpatient hospitalization
or prolongation of existing hospi­
talization,
- 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, observa­
tions, or other activities in a clinical
trial necessary for the reconstruc­
tion and evaluation of the trial.
Source data are contained in source
documents (original records or cer­
tified copies).

1.52 Source Documents
Original documents, data, and
records (eg. hospital records, clinical
and office charts, laboratory notes,
memoranda, subjects’ diaries or eval­
uation checklists, pharmacy dis­
pensing records, recorded data from
automated instruments,copies or
transcriptions certified after verifica­
tion 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

7

I CH Guideline for GCP

1.57 Subject/Trial Subject

involved in the clinical trial).

An individual who participates in a
1.53 Sponsor

clinical trial, either as a recipient of

An individual, company, institution,

the investigational product(s) or as a

or organization which takes respon­

control.

sibility for the initiation, manage­
ment, and/or financing of a clinical

1.58 Subject Identification

trial.

Code
A unique identifier assigned by the

1.54 Sponsor-Investigator

investigator to each trial subject to
protect the subject’s identity and

An individual who both initiates and

conducts, alone or with others, a

used in lieu of the subject’s name

clinical trial, and under whose imme­

when the investigator reports

diate direction the investigational

adverse events and/or other trial

product is administered to, dis­

related data.

pensed to, or used by a subject. The
term does not include any person

1.59 Trial Site

other than an individual (eg. it does

The location(s) where trial-related

not include a corporation or an

activities are actually conducted.

agency). The obligations of a spon­

sor-investigator include both those

1.60 Unexpected Adverse

of a sponsor and those of an investi­

Drug Reaction

gator.

An adverse reaction, the nature or

1.55 Standard Operating

severity of which is not consistent
with the applicable product informa­

Procedures (SOPs)

tion (eg. Investigator’s Brochure for

Detailed,
to

written

achieve

instructions

an unapproved investigational prod­

of the

uct or package insert/summary of
product characteristics for an

uniformity

performance of a specific function.

approved product) (see the ICH

1.56 Subinvestigator
Any individual member of the clinical

Guideline for Clinical Safety Data

trial team designated and supervised

Standards for Expedited Reporting).

Management:

Definitions

and

by the investigator at a trial site to
perform critical trial-related proce­

1.61 Vulnerable Subjects

dures and/or to make important

Individuals whose willingness to vol­

trial-related decisions (eg. associates,
residents, research fellows). See also

unteer in a clinical trial may be undu­

Investigator.

ly influenced by the expectation,
whether justified or not, of benefits
associated with participation, or of a

8

Glossary

retaliatory response from senior
members of a hierarchy in case of
refusal to participate. Examples are
members of a group with a hierar­
chical structure, such as medical,
pharmacy, dental, and nursing stu­
dents, subordinate hospital and labo­
ratory personnel, employees of the
pharmaceutical industry, members of
the armed forces, and persons kept
in detention. Other vulnerable sub­
jects include patients with incurable
diseases, persons in nursing homes,
unemployed or impoverished per­
sons, patients in emergency situa­
tions, ethnic minority groups, home­
less 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.

9

ICH Guideline for GCP

2. THE PRINCIPLES OF ICH GCP
2.1 Clinical trials should be conduct­
ed in accordance with the ethical
principles that have their origin in the
Declaration of Helsinki, and that are
consistent with GCP and the applica­
ble regulatory requirement(s).

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 con­
ducting a trial should be qualified by
education, training, and experience
to perform his or her respective task(s).

2.2 Before a trial is initiated, fore­
seeable risks and inconveniences
should be weighed against the antici­
pated benefit for the individual trial
subject and society. A trial should be
initiated and continued only if the
anticipated benefits justify the risks.

2.9 Freely given informed consent
should be obtained from every sub­
ject prior to clinical trial participation.

2.3 The rights, safety, and well-being
of the trial subjects are the most
important considerations and should
prevail over interests of science and
society.

2.10 All clinical trial information
should be recorded, handled, and
stored in a way that allows its accu­
rate reporting, interpretation and
verification.

2.4 The available nonclinical and clin­
ical information on an investigational
product should be adequate to sup­
port the proposed clinical trial.

2.1 I The confidentiality of records
that could identify subjects should be
protected, respecting the privacy
and confidentiality rules in accor­
dance with the applicable regulatory
requirement(s).

2.5 Clinical trials should be scientifi­
cally sound, and described in a clear,
detailed protocol.

2.6 A trial should be conducted in
compliance with the protocol that
has received prior institutional
review board (IRB)/independent
ethics committee (IEC) approval/
favourable opinion.
2.7 The medical care given to, and

10

2.12 Investigational products should
be manufactured, handled, and
stored in accordance with applicable
good manufacturing practice (GMP).
They should be used in accordance
with the approved protocol.
2.13 Systems with procedures that
assure the quality of every aspect of
the trial should be implemented.

Institutional Review Board/lndependent Ethics Committee

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 con­
sent form updates that the investiga­
tor proposes for use in the trial, sub­
ject recruitment procedures (eg.
advertisements), written information
to be provided to subjects,
Investigator’s Brochure (IB), available
safety information, information
about payments and compensation
available to subjects, the investiga­
tor’s current curriculum vitae and/or
other documentation evidencing
qualifications, and any other docu­
ments that the IRB/IEC may need to
fulfil its responsibilities.
The IRB/IEC should review a pro­
posed clinical trial within a reason­
able time and document its views in
writing, clearly identifying the trial,
the documents reviewed and the
dates for the following:
- approval/favourable opinion;

- modifications required prior to
its approval/favourable opinion;
- disapproval/negative opinion; and
- termination/suspension of any
prior approval/favourable opinion.
3.1.3 The IRB/IEC should consider
the qualifications of the investigator
for the proposed trial, as document­
ed by a current curriculum vitae
and/or by any other relevant docu­
mentation 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 pro­
tection 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

11

ICH Guideline for GCP

the proposed protocol and/or other
document(s) adequately addresses
relevant ethical concerns and meets
applicable regulatory requirements
for such trials.
3.1.7 Where the protocol indicates
that prior consent of the trial subject
or the subject’s legally acceptable
representative is not possible (see
4.8.15), the IRB/IEC should deter­
mine that the proposed protocol
and/or other document(s) adquately
addresses relevant ethical concerns
and meets applicable regulatory
requirements for such trials (ie. in
emergency situations).

3.1.8 The IRB/IEC should review
both the amount and method of pay­
ment to subjects to assure that nei­
ther presents problems of coercion
or undue influence on the trial sub­
jects. Payments to a subject should
be prorated and not wholly contin­
gent on completion of the trial by
the subject.

3.1.9 The IRB/IEC should ensure
that information regarding payment
to subjects, including the methods,
amounts, and schedule of payment
to trial subjects, is set forth in the
written informed consent form and
any other written information to be
provided to subjects. The way pay­
ment will be prorated should be
specified.

12

3.2 Composition, Functions
and Operations
3.2.1 The IRB/IEC should consist of
a reasonable number of members,
who collectively have the qualifica­
tions and experience to review and
evaluate the science, medical
aspects, and ethics of the proposed
trial. It is recommended that the
IRB/IEC should include:
(a) At least five members.
(b) At least one member whose pri­
mary 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-relat­
ed 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 oper­
ating procedures, should maintain
written records of its activities and
minutes of its meetings, and should
comply with GCP and with the appli­
cable regulatory requirement(s).
3.2.3 An IRB/IEC should make its
decisions at announced meetings at
which at least a quorum, as stipulat­
ed in its written operating
procedures, is present.

Institutional Review Board/lndependent Ethics Committee

3.2.4 Only members who partici­
pate in the IRB/IEC review and dis­
cussion should vote/provide their
opinion and/or advise.

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.

3.2.5 The investigator may provide
information on any aspect of the
trial, but should not participate in
the deliberations of the IRB/IEC or
in the vote/opinion of the IRB/IEC.

3.3.7 Specifying that no deviations
from, or changes of, the protocol
should be initiated without prior
written IRB/IEC approval/favourable
opinion of an appropriate amend­
ment, except when necessary to
eliminate immediate hazards to
the subjects or when the change(s)
involves only logistical or administra­
tive aspects of the trial (eg. change of
monitor(s), telephone number(s))
(see 4.5.2).

3.2.6 An IRB/IEC may invite non­
members with expertise in special
areas for assistance.
3.3 Procedures
The IRB/IEC should establish, docu­
ment in writing, and follow its proce­
dures, which should include:

3.3.1 Determining its composition
(names and qualifications of the
members) and the authority under
which it is established.

3.3.2 Scheduling, notifying its mem­
bers of, and conducting its meetings.
3.3.3 Conducting initial and continu­
ing review of trials.
3.3.4 Determining the frequency of
continuing review, as appropriate.

3.3.5 Providing, according to the
applicable regulatory requirements,
expedited review and approval/favourable opinion of minor change(s)
in ongoing trials that have the app­
roval/ favourable opinion of the IRB/IEC.

3.3.8 Specifying that the investigator
should promptly report to the
IRB/IEC:

(a) Deviations from, or changes of,
the protocol to eliminate imme­
diate hazards to the trial sub­
jects (see 3.3.7, 4.5.2, 4.5.4).
(b) Changes increasing the risk to
subjects and/or affecting signifi­
cantly 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 sub­
jects or the conduct of the trial.

3.3.9 Ensuring that the IRB/IEC
promptly notify in writing th6 investigator/institution concerning:

13

ICH Guideline for GCP

(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 rele' vant records (eg. written proce­
dures, membership lists, lists of
occupations/affiliations of members,
submitted documents, minutes of
meetings, and correspondence) for a
period of at least 3 years after com­
pletion of the trial and make them
available upon request from the reg­
ulatory authority(ies).
The IRB/IEC may be asked by inves­
tigators, sponsors or regulatory
authorities to provide its written
procedures and membership lists.

14

Investigator

4. INVESTIGATOR
4.1 Investigator’s

4.1.5 The investigator should main­

Qualifications and

tain a list of appropriately qualified

Agreements

persons to whom the investigator has

4.1.1 The investigator(s) should be

delegated significant trial-related duties.

qualified by education, training, and
experience to assume responsibility
for the proper conduct of the trial,

4.2.1 The investigator should be

should meet all the qualifications

able to demonstrate (eg. based on

specified by the applicable regulatory

retrospective data) a potential for

4.2 Adequate Resources

requirement(s), and should provide

recruiting the required number of

evidence of such qualifications

suitable subjects within the agreed

through up-to-date curriculum vitae

recruitment period.

and/or other relevant documenta­
tion requested by the sponsor, the
IRB/IEC, and/or the regulatory

authority(ies).

4.2.2 The investigator should have

sufficient time to properly conduct
and complete the trial within the
agreed trial period.

4.1.2 The investigator should be

thoroughly familiar with the appro­

4.2.3 The investigator should have

priate use of the investigational

available an adequate number of

product(s), as described in the pro­

qualified staff and adequate facilities

tocol, in the current Investigator’s

for the foreseen duration of the trial

Brochure, in the product informa­

to conduct the trial properly and

tion and in other information

safely.

sources provided by the sponsor.

4.2.4 The investigator should ensure

4.1.3 The investigator should be

that all persons assisting with the

aware of, and should comply with,

trial are adequately informed about

GCP and the applicable regulatory

the protocol, the investigational product(s), and their trial-related duties

requirements.

and functions.
4.1.4 The investigator/institution
should permit monitoring and audit­

4.3 Medical Care of Trial

ing by the sponsor, and inspection by

Subjects

the appropriate regulatory authori-

4.3.1 A qualified physician (or den­

ty(ies).

tist, when appropriate), who is an

investigator or a sub-investigator for

15

ICH Guideline for GCP

the trial, should be responsible for
all trial-related medical (or dental)
decisions.

4.3.2 During and following a sub­
ject’s participation in a trial, the
investigator/institution should ensure
that adequate medical care is provid­
ed to a subject for any adverse
events, including clinically significant
laboratory values, related to the
trial. The investigator/institution
should inform a subject when medi­
cal care is needed for intercurrent
illness(es) of which the investigator
becomes aware.
4.3.3 It is recommended that the
investigator inform the subject’s pri­
mary physician about the subject’s
participation in the trial if the subject
has a primary physician and if the
subject agrees to the primary physi­
cian 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

16

informed consent form, consent
form updates, subject recruitment
procedures (eg. 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, the inves­
tigator/institution should provide the
IRB/IEC with a current copy of the
Investigator’s Brochure. If the
Investigator’s Brochure is updated
during the trial, the investigator/insti­
tution should supply a copy of the
updated Investigator’s Brochure to
the IRB/IEC.
4.4.3 During the trial the investiga­
tor/ 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 compli­
ance with the protocol agreed to by
the sponsor and, if required, by the
regulatory authority(ies) and which
was given approval/favourable opin­
ion by the IRB/IEC. The investigator/
institution and the sponsor should
sign the protocol, or an alternative
contract, to confirm agreement.
4.5.2 The investigator should not
implement any deviation from, or
changes of the protocol without
agreement by the sponsor and prior
review and documented approval/

Investigator

favourable opinion from the IRB/IEC
of an amendment, except where
necessary to eliminate an immediate
hazard(s) to trial subjects, or when
the change(s) involves only logistical
or administrative aspects of the trial
(eg. change in monitor(s), change of
telephone number(s)).
4.5.3 The investigator, or person
designated by the investigator,
should document and explain any
deviation from the approved proto­
col.
4.5.4 The investigator may imple­
ment a deviation from, or a change
of, the protocol to eliminate an
immediate hazard(s) to trial subjects
without prior IRB/IEC approval/
favourable opinion. As soon as possi­
ble, the implemented deviation or
change, the reasons for it, and, if
appropriate, the proposed protocol
amendment(s) should be submitted:
(a) to the IRB/IEC for review and
approval/favourable opinion,
(b) to the sponsor for agreement
and, if required,
(c) to the regulatory authority(ies).

4.6 Investigational Product(s)
4.6.1 Responsibility for investiga­
tional product(s) accountability at
the trial site(s) rests with the investi­
gator/institution.

4.6.2 Where allowed/required, the
investigator/institution may/should
assign some or all of the investiga-

tor’s/institution’s duties for investiga­
tional product(s) accountability at
the trial site(s) to an appropriate
pharmacist or another appropriate
individual who is under the supervi­
sion of the investigator/institution.

4.6.3 The investigator/institution
and/or a pharmacist or othei1, appro­
priate individual, who is designated
by the investigator/institution, should
maintain records of the product’s
delivery to the trial site, the inven­
tory at the site, the use by each sub­
ject, and the return to the sponsor
or alternative disposition of unused
product(s). These records should
include dates, quantities, batch/serial
numbers, expiration dates (if applic­
able), and the unique code numbers
assigned to the investigational product(s) and trial subjects. Investi­
gators should maintain records that
document adequately that the sub­
jects were provided the doses speci­
fied 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 regula­
tory requirement(s).
4.6.5 The investigator should ensure
that the investigational product(s)
are used only in accordance with the
approved protocol.

17

ICH Guideline for GCP

4.6.6 The investigator, or a person
designated by the investigator/institution, should explain the correct
use of the investigational product(s)
to each subject and should check, at
intervals appropriate for the trial,
that each subject is following the
instructions properly.

4.7 Randomization
Procedures and Unblinding
The investigator should follow the
trial’s randomization procedures, if
any, and should ensure that the code
is broken only in accordance with
the protocol. If the trial is blinded,
the investigator should promptly
document and explain to the spon­
sor any premature unblinding (eg.
accidental unblinding, unblinding due
to a serious adverse event) of the
investigational product(s).
4.8 Informed Consent of Trial
Subjects
4.8.1 In obtaining and documenting
informed consent, the investigator
should comply with the applicable

4.8.2 The written informed consent
form and any other written informa­
tion to be provided to subjects
should be revised whenever impor­
tant new information becomes avail­
able that may be relevant to the sub­
ject’s consent. Any revised written
informed consent form, and written
information should receive the
IRB/IEC’s approval/favourable opin­
ion in advance of use. The subject or
the subject’s legally acceptable rep­
resentative should be informed in a
timely manner if new information
becomes available that may be rele­
vant to the subject’s willingness to
continue participation in the trial.
The communication of this informa­
tion should be documented.

4.8.3 Neither the investigator, nor
the trial staff, should coerce or
unduly influence a subject to partici­
pate or to continue to participate in
a trial.
4.8.4 None of the oral and written
information concerning the trial,

regulatory requirement(s), and

including the written informed con­

should adhere to GCP and to the
ethical principles that have their ori­
gin in the Declaration of Helsinki.
Prior to the beginning of the trial,
the investigator should have the
IRB/IEC’s
written
approval/
favourable opinion of the written
informed consent form and any
other written information to be pro­
vided to subjects.

sent form, should contain any lan­
guage that causes the subject or the
subject’s legally acceptable represen­
tative to waive or to appear to waive
any legal rights, or that releases or
appears to release the investigator,
the institution, the sponsor, or their
agents from liability for negligence.

18

4.8.5 The investigator, or a person
designated by the investigator,

Investigator

should fully inform the subject or, if
the subject is unable to provide
informed consent, the subject’s legal­
ly acceptable representative, of all
pertinent aspects of the trial includ­
ing the written information given
approval/favourable opinion by the
IRB/IEC.
4.8.6 The language used in the oral
and written information about the
trial, including the written informed
consent form, should be as non­
technical as practical and should be
understandable to the subject or the
subject’s legally acceptable represen­
tative and the impartial witness,
where applicable.

4.8.7 Before informed consent may
be obtained, the investigator, or a
person designated by the investiga­
tor, should provide the subject or
the subject’s legally acceptable
representative ample time and
opportunity to inquire about details
of the trial and to decide whether or
not to participate in the trial. All
questions about the trial should be
answered to the satisfaction of the
subject or the subject’s legally
acceptable representative.

4.8.8 Prior to a subject’s participation
in the trial, the written informed con­
sent form should be signed and per­
sonally dated by the subject or by the
subject’s legally acceptable representa­
tive, and by the person who conduct­
ed 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 wit­
ness should be present during the
entire informed consent discussion.
After the written informed consent
form and any other written informa­
tion to be provided to subjects, is
read and explained to the subject or
the subject’s legally acceptable rep­
resentative, and after the subject or
the subject’s legally acceptable
representative has orally consented
to the subject’s participation in the
trial and, if capable of doing so, has
signed and personally dated the
informed consent form, the witness
should sign and personally date the
consent form. By signing the consent
form, the witness attests that the
information in the consent form and
any other written information was
accurately explained to, and appar­
ently understood by, the subject or
the subject’s legally acceptable rep­
resentative, and that informed con­
sent 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 any other written
information to be provided to sub­
jects should include explanations of
the following:
(a) That the trial involves research.
(b) The purpose of the trial.
(c) The trial treatment(s) and the
probability for random assign-

19

ICH Guideline for GOP

merit to each treatment.

granted direct access to the sub­

(d) The trial procedures to be fol­

ject’s original medical records

lowed, including all invasive

for verification of clinical trial

procedures.

procedures and/or data, without

(e) The subject’s responsibilities.

violating the confidentiality of

(f) Those aspects of the trial that

the subject, to the extent per­

are experimental.

mitted by the applicable laws and

(g) The reasonably foreseeable risks

regulations and that, by signing a

or inconveniences to the subject

written informed consent form,

and, when applicable, to an

the subject or the subject’s legal­

embryo, fetus, or nursing infant.
(h) The reasonably expected bene­

(i)

fits. When there is no intended

(o) That records identifying the sub­

clinical benefit to the subject, the

ject will be kept confidential and,

subject should be made aware of

to the extent permitted by the

this.

applicable laws and/or regu­

The alternative procedure(s) or

lations, will not be made publicly

course(s) of treatment that may

available. If the results of the

be available to the subject, and

trial are published, the subject’s

their important potential bene­

fits and risks.
(j)

ly acceptable representative is
authorizing such access.

identity will remain confidential.
(p) That the subject or the subject’s

The compensation and/or treat­

legally acceptable representative

ment available to the subject in

will be informed in a timely man­

the event of trial-related injury.

ner if information becomes avail­

(k) The anticipated prorated pay­

able that may be relevant to the

ment, if any, to the subject for

subject’s willingness to continue

participating in the trial.

participation in the trial.

The anticipated expenses, if any,

(q) The person(s) to contact for fur­

to the subject for participating in
the trial.

ther information regarding the
trial and the rights of trial sub­

(m) That the subject’s participation

jects, and whom to contact in

(l)

in the trial is voluntary and that

the event of trial-related injury.

the subject may refuse to partici­

(0 The foreseeable circumstances

pate or withdraw from the trial,

and/or reasons under which the

at any time, without penalty or

subject’s participation in the trial

loss of benefits to which the sub­

ject is otherwise entitled.

may be terminated.
(s) The expected duration of the

(n) That the monitor(s), the audi-

subject’s participation in the trial.

tor(s), the IRB/IEC, and the reg­

(t) The approximate number of

ulatory authority(ies) will be

subjects involved in the trial.

20

Investigator

4.8.1 I Prior to participation in the

sent of a legally acceptable represen­

trial, the subject or the subject’s

tative provided the following condi­

legally acceptable representative

tions are fulfilled:

should receive a copy of the signed

(a) The objectives of the trial can

and dated written informed consent

not be met by means of a trial in

form and any other written informa­

subjects who can give informed

tion provided to the subjects. During

consent personally.
(b) The foreseeable risks to the sub­

a subject’s participation in the trial,
acceptable representative should

jects are low.
(c) The negative impact on the sub­

receive a copy of the signed and

ject’s well-being is minimized and

dated consent form updates and a

low.
(d) The trial is not prohibited by

the subject or the subject’s legally

copy of any amendments to the
written information provided to sub­

jects.

law.

(e) The approval/favourable opinion

of the IR.B/IEC is expressly

4.8.12 When a clinical trial (thera­

sought on the inclusion of such

peutic dr non-therapeutic) includes

subjects,

subjects who can only be enrolled in

approval/favourable opinion cov­

the trial with the consent of the sub­

ers this aspect.

ject’s legally acceptable representa­
tive (eg. minors, or patients with

and

the

written

severe dementia), the subject should

Such trials, unless an exception is
justified, should be conducted in

be informed about the trial to the

patients having a disease or condi­

extent compatible with the subject’s

tion for which the investigational

understanding and, if capable, the

product is intended. Subjects in

subject should sign and personally

these trials should be particularly

date the written informed consent.

closely monitored and should be

withdrawn if they appear to be
4.8.13 Except as described in 4.8.14,

unduly distressed.

a non-therapeutic trial (ie. a trial in

which there is no anticipated direct
clinical benefit to the subject), should

4.8.15 In emergency situations,
when prior consent of the subject is

be conducted in subjects who per­

not possible, the consent of the sub­

sonally give consent and who sign

ject’s legally acceptable representa­

and date the written informed con­

tive, if present, should be requested.

sent form.

When prior consent of the subject is

not possible, and the subject’s legally
4.8.14 Non-therapeutic trials may

acceptable representative is not

be conducted in subjects with con­

available, enrolment of the subject

21

ICH Guideline for GCP

should require measures described

dures to assure that changes or cor­

in the protocol and/or elsewhere,

rections in CRFs made by sponsor’s

with documented approval/favour-

designated representatives are docu­

able opinion by the IRB/IEC, to pro­

mented, are necessary, and are

tect the rights, safety and well-being

endorsed by the investigator. The

of the subject and to ensure compli­

investigator should retain records of

ance with applicable regulatory

the changes and corrections.

requirements. The subject or the
subject’s legally acceptable represen-

4.9.4 The investigator/institution

• tative should be informed about the

should maintain the trial documents

trial as soon as possible and consent

as specified in Essential Documents

to continue and other consent as

for the Conduct of a Clinical Trial

appropriate (see 4.8.10) should be

(see 8.) and as required by the appli­

requested.

cable regulatory requirement(s). The

4.9 Records and Reports

measures to prevent accidental or

investigator/institution should take

4.9.1 The investigator should ensure

premature destruction of these doc­

the accuracy, completeness, legibility,

uments.

and timeliness of the data reported

to the sponsor in the CRFs and n all
required reports.

4.9.5 Essential documents should be
retained until at least 2 years after

the last approval of a marketing
4.9.2 Data reported on the CRF,

application in an ICH region and

that are derived from source locu-

until there are no pending or con­

ments, should be consistent wr h the

templated marketing applications in

source documents or the discrepan­

an ICH region or at least 2 years

cies should be explained.

have elapsed since the formal dis­

4.9.3 Any change or correction to a

continuation of clinical development
of the investigational product. These

CRF should be dated, initialed, and

documents should be retained for a

explained (if necessary) and should

longer period however if required by

not obscure the original entry (ie. an

the applicable regulatory require­

audit trail should be maintained); this

ments or by an agreement with the

applies to both written and electron­

sponsor. It is the responsibility of

ic changes or corrections (see 5.18.4

the sponsor to inform the investiga­

(n)). Sponsors should provide guid­

tor/institution as to when these doc­

ance to investigators and/o • the

uments no longer need to be

investigators’ designated representa­

retained (see 5.5.12).

tives on making such corrections.

Sponsors should have written proce-

22

4.9.6 The financial aspects of the

Investigator

trial should be documented in an

names, personal identification num­

agreement between the sponsor and

bers, and/or addresses. The investi­

the investigator/institution.

gator should also comply with the

applicable regulatory requirement(s)
4.9.7 Upon request of the monitor,

related to the reporting of unexpect­

auditor, IRB/IEC, or regulatory

ed serious adverse drug reactions to

authority, the investigator/institution

the regulatory authority(ies) and the

should make available for direct

IRB/IEC.

access all requested trial-related
records.

4.1 1.2 Adverse events and/or labo­

4.10 Progress Reports

protocol as critical to safety evalua­

4.10.1 The investigator should sub­

tions should be reported to the

mit written summaries of the trial

sponsor according to the reporting

status to the IRB/IEC annually, or

requirements and within the time

ratory abnormalities identified in the

more frequently, if requested by the

periods specified by the sponsor in

IRB/IEC.

the protocol.

4.10.2 The investigator should

4.1 1.3 For reported deaths, the

promptly provide written reports to

investigator should supply the spon­

the sponsor, the IRB/IEC (see 3.3.8)

sor and the IRB/IEC with any addi­

and, where applicable, the institution

tional requested information (eg.

on any changes significantly affecting

autopsy reports and terminal medi­

the conduct of the trial, and/or

cal reports).

increasing the risk to subjects.
4.12 Premature Termination

4.1 I Safety Reporting

or Suspension of a Trial

4.1 1.1 All serious adverse events
(SAEs) should be reported immedi­

or suspended for any reason, the

ately to the sponsor except for

investigator/institution

those SAEs that the protocol or

promptly inform the trial subjects,

other document (eg. Investigator’s

should assure appropriate therapy

Brochure) identifies as not needing

and follow-up for the subjects, and,

immediate reporting. The immediate

where required by the applicable

reports should be followed promptly

regulatory requirement(s), should

by detailed, written reports. The

inform the regulatory authority(ies).

immediate and follow-up reports

In addition:

If the trial is prematurely terminated
should

should identify subjects by unique
code numbers assigned to the trial

4.12.1 If the investigator terminates

subjects rather than by the subjects’

or suspends a trial without prior

23

I CH Guideline for GCP

agreement of the sponsor, the inves­

tigator should inform the institution

where applicable, and the investigator/institution should promptly

inform the sponsor and the IRB/IEC,
and should provide the sponsor and
the IRB/IEC a detailed written expla­
nation of the termination or suspen­

sion.

4.12.2 If the sponsor terminates or

suspends a trial (see 5.21), the inves­
tigator should promptly inform the

institution where applicable and the

investigator/institution

should

promptly inform the IRB/IEC and
provide the IRB/IEC a detailed writ­

ten explanation of the termination
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
the investigator/institution should
promptly notify the sponsor and
provide the sponsor with a detailed
written explanation of the termina­
tion 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 author-

ity(ies) with any reports required.

24

Sponsor

5. SPONSOR
5.1 Quality Assurance and
Quality Control
5.1.1 The sponsor is responsible for
implementing and maintaining quality
assurance and quality control sys­
tems with written SOPs to ensure
that trials are conducted and data
are generated, documented (record­
ed), and reported in compliance with
the protocol, GCP, and the applica­
ble 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 for the
purpose of monitoring and auditing
by the sponsor, and inspection by
domestic and foreign regulatory
authorities.

5.1.3 Quality control should be
applied to each stage of data han­
dling to ensure that all data are reli­
able and have been processed cor­
rectly.
5.1.4 Agreements, made by the
sponsor with the investigator/institution and any other parties involved
with the clinical trial, should be in
writing, as part of the protocol or in
a separate agreement.

5.2 Contract Research
Organization (CRO)

5.2.1 A sponsor may transfer any or
all of the sponsor’s trial-related
duties and functions to a CRO, but
the ultimate responsibility for the
quality and integrity of the trial data
always resides with the sponsor. The
CRO should implement quality
assurance and quality control.
5.2.2 Any trial-related duty and
function that is transferred to and
assumed by a CRO should be speci­
fied in writing.
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 appro­
priately qualified medical personnel
who will be readily available to
advise on trial related medical ques­
tions or problems. If necessary, out­
side consultant(s) may be appointed
for this purpose.

5.4 Trial Design
5.4.1 The sponsor should utilize
qualified individuals (eg. biostatisti-

25

ICH Guideline for GCP

cians, clinical pharmacologists, and
physicians) as appropriate, through­

tronic trial data systems, the sponsor

should:

out all stages of the trial process,
from designing the protocol and

(a) Ensure and document that the

CRFs and planning the analyses to

tem(s) conforms to the spon­

electronic data processing sys-

analyzing and preparing interim and

sor’s established requirements

final clinical trial reports.

for completeness, accuracy, reli­

ability, and consistent intended

5.4.2 For further guidance: Clinical
Trial Protocol and Protocol Amend­

ments) (see 6.), the ICH Guideline

for Structure and Content of Clinical

performance (ie. validation).
(b) Maintains SOPs for using these

systems.
(c) Ensure that the systems are

Study Reports, and other appropri­

designed to permit data changes

ate ICH guidance on trial design,

in such a way that the data

protocol and conduct.

changes are documented and

that there is no deletion of

5.5 Trial Management, Data

entered data (ie. maintain an

Handling, and Record Keeping

audit trail, data trail, edit trail).

5.5.1 The sponsor should utilize

(d) Maintain a security system that

appropriately qualified individuals to

prevents unauthorized access to
the data.

supervise the overall conduct of the
trial, to handle the data, to verify the

(e) Maintain a list of the individuals

data, to conduct the statistical analy­

who are authorized to make

ses, and to prepare the trial reports.

data changes (see 4.1.5 and

4.9.3).
5.5.2 The sponsor may consider

Maintain adequate backup of the

(f)

establishing an independent datamonitoring committee (IDMC) to

assess the progress of a clinical trial,
including the safety data and the crit­

data.
(g) Safeguard the blinding, if any (eg.
maintain the blinding during data

entry and processing).

ical efficacy endpoints at intervals,
and to recommend to the sponsor

5.5.4 If data are transformed during

whether to continue, modify, or
stop a trial. The IDMC should have

processing, it should always be possi­
ble to compare the original data and

written operating procedures and

observations with the processed

maintain written records of all its

data.

meetings.

5.5.5 The sponsor should use an

5.5.3 When using electronic trial

unambiguous subject identification

data handling and/or remote elec-

code (see 1.58) that allows identifi-

26

I

Sponsor

cation of all the data reported for
each subject.

5.5.6 The sponsor, or other owners
of the data, should retain all of the
sponsor-specific essential documents
pertaining to the trial (see 8.
Essential Documents for the
Conduct of a Clinical Trial).
5.5.7 The sponsor should retain all
sponsor-specific essential documents
in conformance with the applicable
regulatory requirement(s) of the
country(ies) where the product is
approved, and/or where the sponsor
intends to apply for approval(s).

5.5.8 If the sponsor discontinues the
clinical development of an investiga­
tional product (ie. for any or all indi­
cations, 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 reg­
ulatory requirement(s).
5.5.9 If the sponsor discontinues the
clinical development of an investiga­
tional product, the sponsor should
notify all the trial investigators/institutions and all the regulatory authorities.

5.5.10 Any transfer of ownership of
the data should be reported to the
appropriate authority(ies), as
required by the applicable regulatory
requirement(s).

5.5.11 The sponsor specific essential
documents should be retained until
at least 2 years after the last
approval of a marketing application
in an ICH region and until there are
no pending or contemplated market­
ing 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 how­
ever if required by the applicable
regulatory requirement(s) or if need­
ed by the sponsor.
5.5.12 The sponsor should inform
the investigator(s)/institution(s) in
writing of the need for record reten­
tion and should notify the investigator(s)/institution(s) in writing when
the trial related records are no
longer needed.

5.6 Investigator Selection
5.6.1 The sponsor is responsible for
selecting the investigator(s)/institution(s). Each investigator should be
qualified by training and experience
and should have adequate resources
(see 4.1, 4.2) to properly conduct
the trial for which the investigator is

selected. If organization of a coordi­
nating 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

27

ICH Guideline for GCP

with an investigator/institution to
conduct a trial, the sponsor should
provide
the
investigator(s)/
institution(s) with the protocol and
an
up-to-date
Investigator’s
Brochure, and should provide suffi­
cient time for the investigator/insti­
tution 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 compli­
ance with GCP, with the applica­
ble regulatory requirement(s)
(see 4.1.3), and with the proto­
col agreed to by the sponsor and
given approval/favourable opin­
ion 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 essen­
tial documents until the sponsor
informs the investigator/institu­
tion 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 docu­
ment, to confirm this agreement.

5.7 Allocation of Duties and
Functions
Prior to initiating a trial, the sponsor
should define, establish, and allocate
all trial-related duties and functions.

28

5.8 Compensation to Subjects
and Investigators
5.8.1 If required by the applicable
regulatory requirement(s), the spon­
sor should provide insurance or
should indemnify (legal and financial
coverage) the investigator/the insti­
tution against claims arising from the
trial, except for claims that arise
from malpractice and/or negligence.
5.8.2 The sponsor’s policies and
procedures should address the costs
of treatment of trial subjects in the
event of trial-related injuries in
accordance with the applicable regu­
latory requirement(s).
5.8.3 When trial subjects receive
compensation, the method and man­
ner of compensation should comply
with applicable regulatory require­
ments).

5.9 Financing
The financial aspects of the trial
should be documented in an agree­
ment between the sponsor and the
investigator/institution.
5.10 Notification/Submission
to Regulatory Authority(ies)
Before initiating the clinical trial(s),
the sponsor (or the sponsor and the
investigator, if required by the appli­
cable regulatory requirement(s))
should submit any required applica­
tion^)
to the appropriate
authority(ies) for review, acceptance,
and/or permission (as required by

Sponsor

the applicable regulatory requirement(s) to begin the trial(s). Any
notification/submission should be
dated and contain sufficient informa­
tion to identify the protocol.

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 Confirmation of Review
by IRB/IEC
5.1 1.1 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 regula­
tions.
(c) Documented IRB/IEC approval/
favourable opinion and, if
requested by the sponsor, a cur­
rent copy of protocol, written
informed consent form(s) and
any other written information to
be provided to subjects, subject
recruiting procedures, and docu­
ments related to payments and
compensation available to the
subjects, and any other docu­
ments that the IRB/IEC may have
requested.

5.11.3 The sponsor should obtain
from the investigator/institution doc­
umentation and dates of any IRB/IEC
reapprovals/re-evaluations with
favourable opinion, and of any with­
drawals or suspensions of approval/
favourable opinion.

5.1 1.2 If the IRB/IEC conditions its
approval/favourable opinion upon
change(s) in any aspect of the trial,
such as modification(s) of the proto­
col, written informed consent form
and any other written information to
be provided to subjects, and/or
other procedures, the sponsor

5.12 Information on
Investigational Product(s)
5.12.1 When planning trials, the
sponsor should ensure that sufficient
safety and efficacy data from nonclinical studies and/or clinical trials are
available to support human exposure
by the route, at the dosages, for the
duration, and in the trial population
to be studied.
5.12.2 The sponsor should update
the Investigator’s Brochure as signifi­
cant new information becomes avail­
able (see 7. Investigator’s Brochure).

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 character­
ized as appropriate to the stage of
development of the product(s), is

29

ICH Guideline for GCP

manufactured in accordance with
any applicable GMP, and is coded
and labelled in a manner that pro­
tects the blinding, if applicable. In
addition, the labelling should comply
with applicable regulatory requirement(s).

(eg. stability, dissolution rate, bio­
availability) needed to assess
whether these changes would signifi­
cantly alter the pharmacokinetic pro­
file of the product should be avail­
able prior to the use of the new for­
mulation in clinical trials.

5.13.2 The sponsor should deter­
mine, for the investigational prod• uct(s), acceptable storage tempera­
tures, storage conditions (eg. pro­
tection from light), storage times,
reconstitution fluids and procedures,
and devices for product infusion, if
any. The sponsor should inform all
involved parties (eg. monitors,
investigators, pharmacists, storage
managers) of these determinations.

5.14 Supplying and Handling
Investigational Product(s)
5.14.1 The sponsor is responsible
for supplying the investigator(s)/institution(s) with the investigational
product(s).

5.13.3
The
investigational
product(s) should be packaged to
prevent contamination and unac­
ceptable deterioration during trans­
port and storage.
5.13.4 In blinded trials, the coding
system for the investigational product(s) should include a mechanism
.
that permits rapid identification of

the product(s) in case of a medical
emergency, but does not permit
undetectable breaks of the blinding.

5.13.5 If significant formulation
changes are made in the investiga­
tional or comparator product(s) dur­
ing the course of clinical develop­
ment, the results of any additional
studies of the formulated product(s)

30

5.14.2 The sponsor should not sup­
ply an investigator/institution with
the investigational product(s) until
the sponsor obtains all required doc­
umentation (eg. approval/favourable
opinion from IRB/IEC and regulatory
authority(ies)).
5.14.3 The sponsor should ensure
that written procedures include
instructions that the investigator/
institution should follow for the han­
dling and storage of investigational
product(s) for the trial and docu­
mentation thereof. The procedures
should address adequate and safe
receipt, handling, storage, dispensing,
retrieval of unused product from
subjects, and return of unused inves­
tigational product(s) to the sponsor
(or alternative disposition if autho­
rized by the sponsor and in compli­
ance with the applicable regulatory
requirement(s)).

Sponsor

5.14.4 The sponsor should:
(a) Ensure timely delivery of investi­
gational product(s) to the
investigator(s).
(b) Maintain records that document
shipment, receipt, disposition,
return, and destruction of the
investigational product(s) (see 8.
Essential Documents for the
Conduct of a Clinical Trial).
(c) Maintain a system for retrieving
investigational products and doc­
umenting this retrieval (eg. for
deficient product recall, reclaim
after trial completion, expired
product reclaim).
(d) Maintain a system for the dispo­
sition of unused investigational
product(s) and for the documen­
tation of this disposition.

5.14.5 The sponsor should:
(a) Take steps to ensure that the
investigational product(s) are
stable over the period of use.
(b) Maintain sufficient quantities of
the investigational product(s)
used in the trials to reconfirm
specifications, should this
become necessary, and maintain
records of batch sample analyses
and characteristics. To the
extent stability permits, samples
should be retained either until
the analyses of the trial data are
complete or as required by the
applicable regulatory requirement(s), whichever represents
the longer retention period.

5.15 Record Access
5.15.1 The sponsor should ensure
that it is specified in the protocol or
other written agreement that the
investigator(s)/institution(s) provide
direct access to source data/documents for trial-related monitoring,
audits, IRB/IEC review, and regulato­
ry 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 trialrelated monitoring, audit, IRB/IEC
review, and regulatory inspection.

5.16 Safety Information
5.16.1 The sponsor is responsible
for the ongoing safety evaluation of
the investigational product(s).

5.16.2 The sponsor should promptly
notify all concerned investigator(s)/
institution(s) and the regulatory
authority(ies) of findings that could
affect adversely the safety of sub­
jects, impact the conduct of the trial,
or alter the IRB/IEC’s approval/
favourable opinion to continue the
trial.
5.17 Adverse Drug Reaction
Reporting
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

\oo
31

ICH Guideline for GCP

are both serious and unexpected.
5.17.2 Such expedited reports
should comply with the applicable
regulatory requirement(s) and with
the ICH Guideline for Clinical Safety
Data Management: Definitions and
Standards for Expedited Reporting.
17.3 The sponsor should submit
to the regulatory authority(ies) all
safety updates and periodic reports,
as required by applicable regulatory
requirement(s).

5.18 Monitoring
5.18.1 Purpose
The purposes of trial monitoring are
to verify that:
(a) The rights and well-being of
human subjects are protected.
(b) The reported trial data are accu­
rate, 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 require­
ments).
5.18.2 Selection and Qualifications
of Monitors
(a) Monitors should be appointed by
the sponsor.
(b) Monitors should be appropriate­
ly trained, and should have the
scientific and/or clinical knowl­
edge needed to monitor the trial
adequately. A monitor’s qualifi-

32

cations should be documented.
(c) Monitors should be thoroughly
familiar with the investigational
product(s), the protocol, written
informed
consent form and any other
written information to be pro­
vided to subjects, the sponsor’s
SOPs, GCP, and the applicable
regulatory requirement(s).
5.18.3 Extent and Nature of
Monitoring
The sponsor should ensure that the
trials are adequately monitored. The
sponsor should determine the
appropriate extent and nature of
monitoring. The determination of
the extent and nature of monitoring
should be based on considerations
such as the objective, purpose,
design, complexity, blinding, size, and
endpoints of the trial. In general
there is a need for on-site monitor­
ing, before, during, and after the
trial; however in exceptional circum­
stances the sponsor may determine
that central monitoring in conjunc­
tion with procedures such as investi­
gators’ training and meetings, and
extensive written guidance can
assure appropriate conduct of the
trial in accordance with GCP.
Statistically controlled sampling may
be an acceptable method for select­
ing the data to be verified.
5.18.4 Monitor’s Responsibilities
The monitor(s) in accordance with
the sponsor’s requirements should

Sponsor

ensure that the trial is conducted
and documented properly by carry­
ing out the following activities when
relevant and necessary to the trial
and the trial site:
(a) Acting as the main line of com­
munication 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, includ­
ing laboratories, equipment, and
staff, are adequate to safely and
properly conduct the trial and
remain adequate throughout the
trial period.
(c) Verifying, for the investigational
product(s):
(i) That storage times and con­
ditions 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 proto­
col specified dose(s).
(iii) That subjects are provided
with necessary instruction
on properly using, handling,
storing, and returning the
investigational product(s).
(iv) That the receipt, use, and
return of the investigational
product(s) at the trial sites
are controlled and docu­
mented adequately.
(v) That the disposition of

unused investigational prod­
uces) at the trial sites com­
plies with applicable regula­
tory requirement(s) and is in
accordance with the sponsor.
(d) Verifying that the investigator
follows the approved protocol
and all approved amendment(s),
if any.
(e) Verifying that written informed
consent was obtained before
each subject’s participation in
the trial.
(f) Ensuring that the investigator
receives
the
current
Investigator’s Brochure, all docu­
ments, and all trial supplies
needed to conduct the trial
properly and to comply with the
applicable regulatory require­
ments).
(g) Ensuring that the investigator
and the investigator’s trial staff
are adequately informed about
the trial.
(h) Verifying that the investigator
and the investigator’s trial staff
are performing the specified trial
functions, in accordance with the
protocol and any other written
agreement between the sponsor
and the investigator/institution,
and have not delegated these
functions to unauthorized indi­
viduals.
(i) Verifying that the investigator is
enroling only eligible subjects.
(j) Reporting the subject recruit­
ment rate.
(k) Verifying that source documents

33

ICH Guideline for GCP

and other trial records are accu­

(n) Informing the investigator of any

rate, complete, kept up-to-date

CRT entry error, omission, or

and maintained.

illegibility. The monitor should

(l) Verifying that the investigator

provides

the

ensure that appropriate correc­

required

tions, additions, or deletions are

reports, notifications, applica­

made, dated, explained (if neces­

tions, and submissions, and that

sary), and initialled by the inves­

these documents are accurate,

tigator or by a member of the

all

complete, timely, legible, dated,

investigator’s trial staff who is

and identify the trial.

authorized to initial CRF changes

(m) Checking the accuracy and com­

for the investigator. This auth­

pleteness of the CRF entries,

orization should be documented.

source documents and other

(o) Determining whether all adverse

trial-related records against each

events (AEs) are appropriately

other. The monitor specifically

reported within the time periods

should verify that:

(i)

required by GCP, the protocol,

The data required by the

the IRB/IEC, the sponsor, and

protocol

the

are

reported

accurately on the CRFs and
are consistent with the

applicable

regulatory

requirement(s).
(p) Determining whether the inves­

tigator is maintaining the essen­

source documents.
(ii) Any dose and/or therapy

tial documents (see 8. Essential

modifications are well docu­

Documents for the Conduct of a

mented for each of the trial

Clinical Trial).

subjects.

(q) Communicating deviations from

(iii) Adverse events, concomi­

the protocol, SOPs, GCP, and

regulatory

tant medications and inter­

the

current illnesses are report­
ed in accordance with the

requirements to the investigator
and taking appropriate action

protocol on the CRFs.

designed to prevent recurrence

(iv) Visits that the subjects fail to

applicable

of the detected deviations.

make, tests that are not con­

ducted, and examinations

5.18.5 Monitoring Procedures

that are not performed are

The monitor(s) should follow the

clearly reported as such on

sponsor’s established written SOPs

the CRFs.

as well as those procedures that are

(v) All

withdrawals

and

dropouts of enrolled subjects

from the trial are reported
and explained on the CRFs.

34

specified by the sponsor for moni­
toring a specific trial.

Sponsor

5.18.6 Monitoring Report
(a) The monitor should submit a
written report to the sponsor
after each trial-site visit or trialrelated communication.
(b) Reports should include the date,
site, name of the monitor, and
name of the investigator or
other individual(s) contacted.
(c) Reports should include a sum­
mary of what the monitor
reviewed and the monitor’s
statements concerning the signif­
icant findings/facts, deviations
and deficiencies, conclusions,
actions taken or to be taken
and/or actions recommended to
secure compliance.
(d) The review and follow-up of the
monitoring report with the
sponsor should be documented
by the sponsor’s designated rep­
resentative.
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 evalu­
ate trial conduct and compliance with
the protocol, SOPs, GCP, and the
applicable regulatory requirements.

5.19.2 Selection and Qualification
ofAuditors
(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 con­
duct audits properly. An audi­
tor’s qualifications should be
documented.
5.19.3 Auditing Procedures
(a) The sponsor should ensure that
the auditing of clinical trials/systems is conducted in accordance
with the sponsor’s written pro­
cedures on what to audit, how
to audit, the frequency of audits,
and the form and content of
audit reports.
(b) The sponsor’s audit plan and
procedures for a trial audit
should be guided by the impor­
tance of the trial to submissions
to regulatory authorities, the
number of subjects in the trial,
the type and complexity of the
trial, the level of risks to the trial
subjects, and any identified problem(s).
(c) The observations and findings of
the auditor(s) should be docu­
mented.
(d) To preserve the independence
and value of the audit function,
the regulatory authority(ies)
should not routinely request the
audit reports. Regulatory

35

I CH Guideline for GCP

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 certifi­
cate.
5.20 Noncompliance
5.20.1 Noncompliance with the pro­
tocol, SOPs, GCP, and/or applicable
regulatory requirement(s) by an
investigator/institution, or by mem­
bers) of the sponsor’s staff should
lead to prompt action by the spon­
sor to secure compliance.
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 participa­
tion in the trial. When an investiga­
tor’s/institution’s participation is ter­
minated because of noncompliance,

IRB/IEC should also be informed
promptly and provided the reason(s)
for the termination or suspension by
the sponsor or by the investigator/
institution, as specified by the appli­
cable regulatory requirement(s).
5.22 Clinical Trial/Study
Reports
Whether the trial is completed or
prematurely terminated, the sponsor
should ensure that the clinical trial
reports are prepared and provided
to the regulatory agency(ies) as
required by the applicable regulatory
requirement(s). The sponsor should
also ensure that the clinical trial
reports in marketing applications
meet the standards of the ICH
Guideline for Structure and Content
of Clinical Study Reports. (NOTE:
The ICH Guideline for Structure and
Content of Clinical Study Reports
specifies that abbreviated study
reports may be acceptable in certain
cases.)

5.23 Multicentre Trials

the sponsor should notify promptly

For multicentre trials, the sponsor

the regulatory authority(ies).

should ensure that:

5.21 Premature Termination
or Suspension of a Trial
If a trial is prematurely terminated
or suspended, the sponsor should
promptly inform the investigators/institutions, and the regulatory
authority(ies) of the termination or
suspension and the reason(s) for the
termination or suspension. The

5.23.1 All investigators conduct the
trial in strict compliance with the
protocol agreed to by the sponsor
and, if required, by the regulatory
authority(ies), and given approval/
favourable opinion by the IRB/IEC.

36

5.23.2 The CRTs are designed to
capture the required data at all mul-

Sponsor

ticentre trial sites. For those investi­
gators 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 coor­
dinating investigator(s) and the other
participating investigators are docu­
mented prior to the start of the trial.
5.23.4 All investigators are given
instructions on following the proto­
col, on complying with a uniform set
of standards for the assessment of
clinical and laboratory findings, and
on completing the CRFs.

5.23.5 Communication between
investigators is facilitated.

37

ICH Guideline for GCP

6. CLINICAL TRIAL PROTOCOL AND
PROTOCOL AMENDMENT(S)
The contents of a trial protocol
should generally include the following
topics. However, site specific infor­
mation may be provided on separate
protocol page(s), or addressed in a
' separate agreement, and some of the
information listed below may be con­
tained in other protocol referenced
documents, such as an Investigator’s
Brochure.
6.1 General Information
6.1.1 Protocol title, protocol identi­
fying number, and date. Any amend­
ments) should also bear the amend­
ment 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 pro­
tocol and the protocol amendment(s) for the sponsor.

6.1.4 Name, title, address, and tele­
phone number(s) of the sponsor’s
medical expert (or dentist when
appropriate) for the trial.

6.1.5 Name and title of the investigator(s) who is (are) responsible for
conducting the trial, and the address
and telephone number(s) of the trial
site(s).

38

6.1.6 Name, title, address, and tele­
phone number(s) of the qualified
physician (or dentist, if applicable),
who is responsible for all trial-site
related medical (or dental) decisions
(if other than investigator).

6.1.7 Name(s) and address(es) of
the clinical laboratory(ies) and other
medical and/or technical depart­
ments) 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 clinical significance and from
clinical trials that are relevant to the
trial.
6.2.3 Summary of the known and
potential risks and benefits, if any, to
human subjects.
6.2.4 Description of and justification
for the route of administration,
dosage, dosage regimen, and treat­
ment period(s).

6.2.5 A statement that the trial will
be conducted in compliance with the
protocol, GCP and the applicable
regulatory requirement(s).

Clinical trial protocol and protocol amendment(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 objec­
tives 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 pri­
mary endpoints and the secondary
endpoints, if any, to be measured
during the trial.

6.4.2 A description of the
type/design of trial to be conducted
(eg. double-blind, placebo-con­
trolled, parallel design) and a
schematic diagram of trial design,
procedures and stages.
6.4.3 A description of the measures
taken to minimize/avoid bias, includ­
ing:
(a) Randomization.
(b) Blinding.
6.4.4 A description of the trial treatment(s) and the dosage and dosage

regimen of the investigational prod­
uces). Also include a description of
the dosage form, packaging, and
labelling of the investigational prod­

uces).
6.4.5 The expected duration of sub­
ject participation, and a description
of the sequence and duration of all
trial periods, including follow-up, if any.
6.4.6 A description of the “stopping
rules" or “discontinuation criteria"
for individual subjects, parts of trial
and entire trial.

6.4.7 Accountability procedures for
the investigational product(s), includ­
ing the placebo(s) and comparator(s), if any.
6.4.8 Maintenance of trial treatment
randomization codes and procedures
for breaking codes.

6.4.9 The identification of any data
to be recorded directly on the CRFs
(ie. no prior written or electronic
record of data), and to be consid­
ered 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 (ie.
terminating investigational product
treatment/trial treatment) and

39

ICH Guideline for GCP

procedures specifying:

6.8 Assessment of Safety

(a) When and how to withdraw

6.8.1 Specification of safety parame­

subjects from the trial/investiga-

ters.

tional product treatment.
(b) The type and timing of the data

6.8.2 The methods and timing for

to be collected for withdrawn

assessing, recording, and analysing

subjects.

safety parameters.

(c) Whether and how subjects are
to be replaced.

6.8.3

Procedures for eliciting

(d) The follow-up for subjects with­

reports of and for recording and

drawn from investigational prod­

reporting adverse event and inter­

uct treatment/trial treatment.

current illnesses.

6.6 Treatment of Subjects

6.8.4 The type and duration of the

6.6.1 The treatment(s) to be admin­

follow-up of subjects after adverse

istered, including the name(s) of all

events.

the product(s), the dose(s), the dos­
ing schedule(s), the route/mode(s) of

6.9 Statistics

administration, and the treatment

6.9.1 A description of the statistical

period(s), including the follow-up

methods to be employed, including

period(s) for subjects for each

timing of any planned interim analy-

investigational product treatment/

sis(ses).

trial treatment group/arm of the
trial.

6.9.2 The number of subjects

planned to be enrolled. In multicen­
6.6.2 Medication(s)/treatment(s)

tre trials, the numbers of enrolled

permitted (including rescue medica­

subjects projected for each trial site

tion) and not permitted before

should be specified. Reason for

and/or during the trial.

choice of sample size, including

reflections on (or calculations of) the

6.6.3 Procedures for monitoring

power of the trial and clinical justifi­

subject compliance.

cation.

6.7 Assessment of Efficacy

6.9.3 The level of significance to be

6.7.1 Specification of the efficacy

used.

parameters.
6.9.4 Criteria for the termination of

6.7.2 Methods and timing for assess­

the trial.

ing, recording, and analysing of efficacy
parameters.

40

6.9.5 Procedure for accounting for

Clinical trial protocol and protocol amendment(s)

missing, unused, and spurious data.
6.9.6 Procedures for reporting any
deviation(s) from the original statisti­
cal plan (any deviation(s) from the
original statistical plan should be
described and justified in protocol
and/or in the final report, as appro­
priate).
b.9.1 The selection of subjects to be
included in the analyses (eg. all ran­
domized subjects, all dosed subjects,
all eligible subjects, evaluable sub­
jects).

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.)

6.10 Direct Access to Source
Data/Documents
The sponsor should ensure that it is
specified in the protocol or other
written agreement that the investigator(s)/institution(s) will permit trialrelated monitoring, audits, IRB/IEC
review, and regulatory inspection(s),
providing direct access to source
data/documents.
6.11 Quality Control and
Quality Assurance
6.12 Ethics
Description of ethical considerations
relating to the trial.

6.13 Data Handling and
Record Keeping
6.14 Financing and Insurance
Financing and insurance if not
addressed in a separate agreement.

- 41

ICH Guideline for GCP

7. INVESTIGATOR’S BROCHURE
7.1 Introduction
available will vary with the stage of
The Investigator’s Brochure (IB) is a
development of the investigational
compilation of the clinical and nonproduct. If the investigational product
clinical data on the investigational
is marketed and its pharmacology is
product(s) that are relevant to the
widely understood by medical practi­
study of the product(s) in human
tioners, an extensive IB may not be
subjects. Its purpose is to provide
necessary. Where permitted by regu­
' the investigators and others involved
latory authorities, a basic product
in the trial with the information to
information brochure, package leaflet,
facilitate their understanding of the
or labelling may be an appropriate
rationale for, and their compliance
alternative, provided that it includes
with, many key features of the pro­
current, comprehensive, and detailed
tocol, such as the dose, dose freinformation on all aspects of the
quency/interval, methods of adminis­
investigational product that might be
tration: and safety monitoring proce­
of importance to the investigator. If a
dures. The IB also provides insight to
marketed product is being studied for
support the clinical management of a new use (ie., a new indication), an
the study subjects during the course
IB specific to that new use should be
of the clinical trial. The information
prepared. The IB should be reviewed
should be presented in a concise,
at least annually and revised as neces­
simple, objective, balanced, and nonsary in compliance with a sponsor’s
promotional form that enables a clin­
written procedures. More frequent
ician, or potential investigator, to
revision may be appropriate depend­
understand it and make his/her own
ing on the stage of development and
unbiased risk-benefit assessment of the generation of relevant new infor­
the appropriateness of the proposed
mation. However, in accordance with
trial. For this reason, a medically
Good Clinical Practice, relevant new
qualified person should generally
information may be so important that
participate in the editing of an IB, but
it should be communicated to the
the contents of the IB should be
investigators, and possibly to the
approved by the disciplines that gen­
Institutional Review Boards (IRBs)/
erated the described data.
Independent Ethics Committees
(lECs) and/or regulatory authorities
This guideline delineates the mini­
before it is included in a revised IB.
mum information that should be
included in an IB and provides sugges­ Generally, the sponsor is responsible
tions for its layout. It is expected that
for ensuring that an up-to-date IB is
the type and extent of information
made available to the investigator(s)

42

Investigator's brochure

and the investigators are responsible
for providing the up-to-date IB to
the responsible IRBs/IECs. In the
case of an investigator sponsored
trial, the sponsor-investigator should
determine whether a brochure is
available from the commercial manu­
facturer. If the investigational prod­
uct is provided by the sponsor-inves­
tigator, then he or she should pro­
vide the necessary information to
the trial personnel. In cases where
preparation of a formal IB is imprac­
tical, the sponsor-investigator should
provide, as a substitute, an expanded
background information section in
the trial protocol that contains the
minimum current information
described in this guideline.

7.2 General Considerations
The IB should include:

7.2.1 Title Page
This should provide the sponsor’s
name, the identity of each investiga­
tional product (ie. research number,
chemical or approved generic name,
and trade name(s) where legally per­
missible and desired by the sponsor),
and the release date. It is also sug­
gested that an edition number, and a
reference to the number and date of
the edition it supersedes, be provided.
An example is given in Appendix I.
7.2.2 Confidentiality Statement
The sponsor may wish to include a
statement instructing the investigator/recipients to treat the IB as a

confidential document for the sole
information and use of the investiga­
tor’s team and the IRB/IEC.

7.3 Contents of the
Investigator’s Brochure
The IB should contain the following
sections, each with literature refer­
ences where appropriate:

7.3.1 Table of Contents
An example of the Table of
Contents is given in Appendix 2

7.3.2 Summary
A brief summary (preferably not
exceeding two pages) should be
given, highlighting the significant
physical, chemical, pharmaceutical,
pharmacological, toxicological,
pharmacokinetic, metabolic, and clin­
ical information available that is rele­
vant to the stage of clinical develop­
ment of the investigational product.
7.3.3 Introduction
A brief introductory statement
should be provided that contains the
chemical name (and generic and
trade name(s) when approved) of
the investigational product(s), all
active ingredients, the investigational
product(s) pharmacological class and
its expected position within this class
(eg. advantages), the rationale for
performing research with the investi­
gational product(s), and the antici­
pated prophylactic, therapeutic, or
diagnostic indication(s). Finally, the
introductory statement should

43

ICH Guideline for GCP

provide the general approach to be
followed in evaluating the investiga­
tional product.
7.3.4 Physical, Chemical, and Pharma­
ceutical Properties and Formulation
A description should be provided of
the investigational product substance(s) (including the chemical
and/or structural formula(e)), and a
brief summary should be given of the
relevant physical, chemical, and phar­
maceutical properties.

To permit appropriate safety mea­
sures to be taken in the course of
the trial, a description of the formulation(s) to be used, including excipi­
ents, should be provided and justi­
fied 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 men­
tioned.
7.3.5 Nonclinical Studies
Introduction:
The results of all relevant nonclinical
pharmacology, toxicology, pharma­
cokinetic, and investigational product
metabolism studies should be pro­
vided in summary form. This summa­
ry should address the methodology
used, the results, and a discussion of
the relevance of the findings to the
investigated therapeutic and the pos­
sible unfavourable and unintended
effects in humans.

44

The information provided may
include the following, as appropriate,
if known/available:
• Species tested
• Number and sex of animals in
each group
• Unit dose (eg. 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 phar­
macological or toxic effects
- Severity or intensity of phar­
macological or toxic effects
- Time to onset of effects
- Reversibility of effects
- Duration of effects
- Dose response

Tabular format/listings should be
used whenever possible to enhance
the clarity of the presentation.
The following sections should dis­
cuss 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 (ie. the
therapeutic index should be dis­
cussed). The relevance of this infor-

Investigator's brochure

mation to the proposed human dos­
ing should be addressed. Whenever
possible, comparisons should be
made in terms of blood/tissue levels
rather than on a mg/kg basis.

(a) Nonclinical Pharmacology
A summary of the pharmacological
aspects of the investigational product
and, where appropriate, its signifi­
cant metabolites studied in animals,
should be included. Such a summary
should incorporate studies that
assess potential therapeutic activity
(eg. efficacy models, receptor bind­
ing, and specificity) as well as those
that assess safety (eg. special studies
to assess pharmacological actions
other than the intended therapeutic
effect(s)).
(b) Pharmacokinetics and Product
Metabolism in Animals
A summary of the pharmacokinetics
and biological transformation and
disposition of the investigational
product in all species studied should
be given. The discussion of the find­
ings should address the absorption
and the local and systemic bioavail­
ability of the investigational product
and its meta-bolites, and their rela­
tionship to the pharmacological and
toxicological findings in animal
species.
(c) Toxicology
A summary of the toxicological
effects found in relevant studies con­
ducted in different animal species

should be described under the fol­
lowing headings where appropriate:
- Single dose
- Repeated dose
- Carcinogenicity
- Special studies (eg. 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 pro­
vided, including information on phar­
macokinetics, metabolism, pharmaco­
dynamics, dose response, safety, effi­
cacy, and other pharmacological activ­
ities. 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 fol­
lowing, if available:
- Pharmacokinetics (including
metabolism, as appropriate, and
absorption, plasma protein bind­
ing, distribution, and elimina­
tion).
- Bioavailability of the investiga-

45

ICH Guideline for GCP

tional product (absolute, where
possible, and/or relative) using a
reference dosage form.
Population subgroups (eg. gen­
der, age, and impaired organ
function).
Interactions (eg. product-prod­
uct interactions and effects of
food).
Other pharmacokinetic data (eg.
results of population studies per­
formed within clinical trial(s).
(b) Safety and Efficacy
A summary of information should be
provided about the investigational
product’s/products’ (including
metabolites, where appropriate)
safety, pharmacodynamics, efficacy,
and dose response that were ob­
tained 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 tri­
als have been completed, the use of
summaries of safety and efficacy
across multiple trials by indication
in subgroups may provide a cleat
presentation of the data. Tabular
summaries of adverse drug reactions
for all the clinical trials (including
those for all the studied indications)
would be useful. Important differ­
ences 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

46

drug reactions to be anticipated on
the basis of prior experiences with
the product under investigation and
with related products. A description
should also be provided of the pre­
cautions or special monitoring to be
done as part of the investigational
use of the product(s).
(c) Marketing Experience
The IB should identify countries
where the investigational product
has been marketed or approved.
Any significant information arising
from the marketed use should be
summarised (eg. formulations,
dosages, routes of administration,
and adverse product reactions). The
IB should also identify all the coun­
tries where the investigational prod­
uct did not receive approval/registration for marketing or was withdrawn
from marketing/registration.
7.3.7 Summary of Data and Guidance
for the Investigator
This section should provide an over­
all discussion of the nonclinical and

clinical data, and should summarise
the information from various
sources on different aspects of the
investigational product(s), wherever
possible. In this way, the investigator
can be provided with the most infor­
mative interpretation of the available
data and with an assessment of the
implications of the information for
ft ’.ure clinical trials.

Where appropriate, the published

Investigator's brochure

reports on related products should
be discussed. This could help the
investigator to anticipate adverse
drug reactions or other problems in
clinical trials.

The overall aim of this section is to
provide the investigator with a clear
understanding of the possible risks
and adverse reactions, and of the
specific tests, observations, and pre­
cautions that may be needed for a
clinical trial. This understanding
should be based on the available
physical, chemical, pharmaceutical,
pharmacological, toxicological, and
clinical information on the investiga­
tional product(s). Guidance should
also be provided to the clinical inves­
tigator on the recognition and treat­
ment of possible overdose and
adverse drug reactions that is based
on previous human experience and
on the pharmacology of the investi­
gational product.

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

Release Date:
Replaces Previous Edition Number:

Date:
7.5 APPENDIX 2:

TABLE OF CONTENTS OF
INVESTIGATOR’S
BROCHURE (Example)
- Confidentiality Statement
(optional)
- Signature Page (optional)
I 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 I. Publications
2. Reports

These references should be found at
the end of each chapter
Appendices (if any)

47

ICH Guideline for GCP

8. ESSENTIAL DOCUMENTS FOR
THE CONDUCT OF A CLINICAL
TRIAL
8.1 Introduction
Essential Documents are those doc­
uments which individually and collec­
tively permit evaluation of the con­
duct of a trial and the quality of the
data produced. These documents
serve to demonstrate the compli­
ance of the investigator, sponsor and
monitor with the standards of Good
Clinical Practice and with all applica­
ble regulatory requirements.

Essential Documents also serve a
number of other important purpos­
es. Filing essential documents at the
investigator/institution and sponso.sites in a timely manner can greatly
assist in the successful managemen:
of a trial by the investigator, sponsor
and monitor. These documents art
also the ones which are usually
audited by the sponsor’s indepen­
dent audit function and inspected by
the regulatory authority(ies) as part
of the process to confirm the validity
of the trial conduct and the integrity
of data collected.
The minimum list of essential docu­
ments which has been developed fol­
lows. The various documents are
grouped in three sections according
to the stage of the trial during which
they will normally be generated

48

I) before the clinical phase of the
trial commences, 2) during the clini­
cal conduct of the trial, and 3) after
completion or termination of the
trial. A description is given of the
purpose of each document, and
whether it should be filed in either
the investigator/institution or spon­
sor files, or both. It is acceptable to
combine some of the documents,
provided the individual elements are
readily identifiable.

Trial master files should be estab­
lished 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/institu­
tion and sponsor files and confirmed
that all necessary documents are in
the appropriate files.
Any or all of the documents
addressed in this guideline may be
subject to, and should be available
for, audit by the sponsor’s auditor
and inspection by the regulatory
authority(ies).

Essential documents for the conduct of a clinical trial

Title of Document

Purpose

Located in Files of
Investigator/
Sponsor
Institution

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
8.2.1 INVESTIGATOR’S
BROCHURE

To document that relevant
and current scientific infor­
mation about the investiga­
tional product has been pro­
vided to the investigator

X

X

8.2.2 SIGNED PROTOCOL
AND AMENDMENTS,
IF ANY, AND SAMPLE
CASE REPORT FORM
(CRF)

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

X

X

To document the informed
consent

X

X

- ANY OTHER
WRITTEN
INFORMATION

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

X

X

-ADVERTISEMENT
FOR SUBJECT
RECRUITMENT
(if used)

To document that recruit­
ment measures are appropri­
ate and not
coercive

X

To document the financial
agreement between the
investigator/institution and
the sponsor for the trial

X

8.2.3 INFORMATION
GIVEN TO TRIAL
SUBJECT
- INFORMED CON­
SENT FORM (including
all applicable transla­
tions)

8.2.4 FINANCIAL ASPECTS
OF THE TRIAL

X

49

ICH Guideline for GCP

Title of Document

Purpose

8.2.5 INSURANCE
STATEMENT
(where required)

To document that compensa­
tion to subject(s) for trialrelated injury will be available

8.2.6 SIGNED AGREEMENT
BETWEEN INVOLVED
PARTIES, eg.:
- investigator/institution and sponsor

To document agreements

Located in Files of
Investigator/
Sponsor
Institution

X

X

X

X

- investigator/institution and CRO
- sponsor and CRO

X

- investigator/institution and authority(ies)
(where required)

X

8.2.7 DATED, DOCU­

MENTED approval;
FAVOURABLE
OPINION OF INSTI­
TUTIONAL REVIEW
BOARD (IRB)ZINDEPENDENT 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)

To document that the trial
has been subject to IRB/IEC
review and given
approval/favourable opinion.
To identify the version num­
ber and date of the document(s)

X

X
(where required)
X
X

X

- subject compensa-

50

1

Essential documents for the conduct of a clinical trial

Title of Document

Purpose

Located in Files of
Investigator/
Sponsor
Institution

tion (if any)
- any other docu­
ments given
approval/favourable
opinion

X

X
(where required)

8.2,8 INSTITUTIONAL
REVIEW BOARD/
INDEPENDENT
ETHICS COMMITTEE
COMPOSITION

To document that the
IRB/IEC is constituted in
agreement with GCP

8.2.9 REGULATORY
AUTHORITY(IES)
AUTHORISATION/
APPROVAL/ NOTIFI­
CATION OF PROTO­
COL (where required)

To document appropriate
authorisation/approval/ notifi­
cation by the regulatory
authority(ies) has been
obtained prior to initiation of
the trial in compliance with
the applicable regulatory
requirement(s)

X
(where
required)

X
(where
required)

8.2. IOCURRICULUM VITAE
AND/OR OTHER
RELEVANT DOCU­
MENTS EVIDENCING
QUALIFICATIONS OF
INVESTIGATOR(S)
AND SUB­
IN VESTIGATOR(S)

To document qualifications
and eligibility to conduct trial
and/or provide medical
supervision of subjects

X

X

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

To document normal values
and/or ranges of the tests

X

X

2___ •

51

ICH Guideline for GCP

Title of Document

Purpose

8.2.12 MEDICAL/LABORA-

To document competence of
facility to perform required
test(s), and support reliability
of results

TORY/TECHNICAL
PROCEDURES/TESTS
- certification or
- accreditation or
- established quality
control and/or
external quality
assessment or
- other validation
(where required)

Located in Files of
Investigator/
Sponsor
Institution

X
(where required)

X

8.2.13 SAMPLE OF LABEL(S)
ATTACHED TO
INVESTIGATIONAL
PRODUCT
CONTAINER(S)

To document compliance
with applicable labelling
regulations and appropriate­
ness of instructions provided
to the subjects

8.2.14 INSTRUCTIONS FOR
HANDLING OF
INVESTIGATIONAL
PRODUCT(S) AND
TRIAL-RELATED
MATERIALS (if not
included in protocol
or Investigator’s
Brochure)

To document instructions
needed to ensure proper
storage, packaging, dispensing
and disposition of investiga­
tional products and trialrelated materials

X

X

8.2.15 SHIPPING RECORDS
FOR INVESTIGA­
TIONAL PRODUCT(S) AND
TRIAL-RELATED
MATERIALS

To document shipment
dates, batch numbers and
method of shipment of inves­
tigational product(s) and
trial-related materials. Allows
tracking of product batch,
review of shipping conditions,
and accountability

X

X

52

X

Essential documents for the conduct of a clinical trial

Located in Files of
Investigator/
Sponsor
Institution

Title of Document

Purpose

8.2.16 CERTIFICATE(S) OF
ANALYSIS OF
INVESTIGATIONAL
PRODUCT(S)
SHIPPED

To document identity, purity,
and strength of investigation­
al product(s) to be used in
the trial

8.2.17 DECODING
PROCEDURES FOR
BLINDED TRIALS

To document how, in case of
an emergency, identity of
blinded investigational prod­
uct can be revealed without
breaking the blind for the
remaining subjects’ treatment

8.2.18 MASTER RANDOMI­
SATION LIST

To document method for
randomisation of trial
population

X
(third party
if applicable)

8.2.19 PRE-TRIAL MONI­
TORING REPORT

To document that the site is
suitable for the trial (may be
combined with 8.2.20)

X

8.2.20 TRIAL INITIATION
MONITORING
REPORT

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

X

X

X

X
(third party
if applicable)

X

8.3 During the Clinical Conduct of the Trial
In addition to having on file the above documents, the following should be added to the files
during the trial as evidence that all new relevant information is documented as it becomes
available

8.3.1

INVESTIGATOR’S
BROCHURE
UPDATES

To document that investiga­
tor is informed in a timely
manner of relevant informa­
tion as it becomes available

X

X

53

I CH Guideline for GCP

Located in Files of
Investigator/
Sponsor
Institution

Title of Document

Purpose

8.3.2 ANY REVISION TO:

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

X

X

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

X

X

- protocol/amend
ment(s) and CRF
- informed consent
form
'

- any other written
information
provided to
subjects
- advertisement for
subject recruitment(if used)

8.3.3

DATED, DOCU­
MENTED
APPROVAL/FAVOURABLE OPINION OF
INSTITUTIONAL
REVIEW BOARD

(IRB)/INDEPENDENT
ETHICS COMMITTEE
(IEC) OF THE
FOLLOWING:
- protocol amend
ment(s)
- revision(s) of:
- informed

consent form
- any other
written
information to
be provided to
the subject
- advertisement
for subject
recruitment
(if used)
- any other
documents

54

Essential documents for the conduct of a clinical trial

Title of Document

Purpose

Located in Files of
Investigator/
Sponsor
Institution

given approval/
favourable
opinion
- continuing review
of trial
(where required)
8.3.4 REGULATORY
AUTHORITY(IES)
AUTHORISATIONS/
APPROVALS/NOTIFICATIONS WHERE
REQUIRED FOR:
- protocol amend
ment(s) and other
documents

To document compliance
with applicable regulatory
requirements

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

(see 8.2.10)

X

X

8.3.6 UPDATES TO NOR­
MAL VALUE(S)/
RANGE(S) FOR
MEDICAL/LABORATORY/TECHNICAL
PROCEDURE(S)/
TEST(S) INCLUDED
IN THE PROTOCOL

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

X

X

8.3.7 UPDATES OF
MEDICAL/ LABORATORY/TECHNICAL
PROCEDURES/
TESTS
- certification or
- accreditation or

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

X
(where required)

X

X
(where required)

X

55

ICH Guideline for GCP

Title of Document

Purpose

Located in Files of
Investigator/
Sponsor
Institution

- established quality
control and/or
external quality
assessment or
- other validation
(where required)

/

8.3.8 DOCUMENTATION
OF INVESTIGA­
TIONAL PROD­
UCES) AND TRIALRELATED MATERI­
ALS SHIPMENT

(see 8.2.15)

8.3.9 CERTIFICATE(S) OF
ANALYSIS FOR
NEW BATCHES OF
INVESTIGATIONAL
PRODUCTS

(see 8.2.16)

X

8.3.10 MONITORING VISIT
REPORTS

To document site visits by,
and findings of, the monitor

X

8.3.11 RELEVANT

To document any agree­
ments or significant discus­
sions regarding trial adminis­
tration, protocol violations,
trial conduct, adverse event
(AE) reporting

X

To document that consent is
obtained in accordance with
GCP and protocol and dated
prior to participation of each
subject in trial. Also to docu­
ment direct access permis­
sion (see 8.2.3)

X

COMMUNICATIONS
OTHER THAN SITE
VISITS
- letters
- meeting notes
- notes of telephone
calls
8.3.12 SIGNED INFORMED
CONSENT FORMS

56

X

X

X

Essential documents for the conduct of a clinical trial

Title of Document

Purpose

Located in Files of
Sponsor
Investigator/
Institution

8.3.13 SOURCE
DOCUMENTS

To document the existence
of the subject and substanti­
ate integrity of trial data col­
lected. To include original
documents related to the
trial, to medical treatment,
and history of subject

X

8.3.14 SIGNED, DATED
AND COMPLETED
CASE REPORT
FORMS (CRF)

To document that the inves­
tigator or authorised mem­
ber of the investigator’s staff
confirms the observations
recorded

X
(copy)

X
(original)

8.3.15 DOCUMENTATION
OF CRF
CORRECTIONS

To document all
changes/additions or correc­
tions made to CRF after
initial data were recorded

X
(copy)

X
(original)

8.3.16 NOTIFICATION BY
ORIGINATING
INVESTIGATOR TO
SPONSOR OF SERI­
OUS ADVERSE
EVENTS AND
RELATED REPORTS

Notification by originating
investigator to sponsor of
serious adverse events and
related reports in accordance
with 4.11

X

X

8.3.17 NOTIFICATION BY
SPONSOR AND/OR
INVESTIGATOR,
WHERE APPLICA­
BLE, TO REGULA­
TORY
AUTHORITY(IES)
AND IRB(S)/IEC(S)
OF UNEXPECTED
SERIOUS ADVERSE
DRUG REACTIONS
AND OF OTHER
SAFETY
INFORMATION

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

X
(where required)

X

57

ICH Guideline for GCP

Title of Document

Purpose

Located in Files of
Investigator/
Sponsor
Institution

8.3.18 NOTIFICATION BY
SPONSOR TO
INVESTIGATORS OF
SAFETY INFORMA­
TION

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

X

8.3.19 INTERIM OR ANNU­
AL REPORTS TO
IRB/IEC AND
AUTHORITY(IES)

Interim or annual reports
provided to IRB/IEC in accor­
dance with 4.10 and to
authority(ies) in accordance
with 5.17.3

X

8.3.20 SUBJECT
SCREENING LOG

To document identification
of subjects who entered
pre-trial screening

X

8.3.21 SUBJECT IDENTIFI­
CATION CODE LIST

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

X

8.3.22 SUBJECT ENROL­
MENT LOG

To document chronological

X

8.3.23 INVESTIGATIONAL
PRODUCTS
ACCOUNTABILITY
AT THE SITE

To document that investiga­
tional product(s) have been
used according to the
protocol

X

X

8.3.24 SIGNATURE SHEET

To document signatures and
initials of all persons autho­
rised to make entries and/or
corrections on CRFs

X

X

58

X

X
(where required)
♦

X
(where required)

enrolment of subjects by trial
number

Essential documents for the conduct of a clinical trial

Title of Document

Purpose

8.3.25 RECORD OF
RETAINED BODY
FLUIDS/TISSUE SAM­
PLES (IF ANY)

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

Located in Files of
Sponsor
Investigator/
Institution

X

X

8.4 After Completion or Termination of the Trial
After completion or termination of the trial, all of the documents identified in sections 8.2

and 8.3 should be in the file together with the following
INVESTIGATIONAL
PRODUCT(S)
ACCOUNTABILITY
AT SITE

To document that the inves­
tigational product(s) have
been used according to the
protocol. To documents the
final accounting of investiga­
tional product(s) received at
the site, dispensed to sub­
jects, returned by the sub­
jects, and returned to spon­
sor

8.4.2 DOCUMENTATION
OF INVESTIGA­
TIONAL PRODUCT
DESTRUCTION

To document destruction of
unused investigational prod­
ucts by sponsor or at site

COMPLETED SUB­
JECT IDENTIFICA­
TION CODE LIST

To permit identification of all
subjects enrolled in the trial
in case follow-up is required.
List should be kept in a confi­
dential manner and for
agreed upon time

8.4.1

8.4.3

X

X
(if destroyed at site)

X

X

X

8.4.4 AUDIT CERTIFICATE
(if available)

To document that audit was
performed

X

8.4.5

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

X

FINAL TRIAL CLOSE­
OUT MONITORING
REPORT

59

ICH Guideline for GCP

Title of Document

Purpose

8.4.6 TREATMENT ALLO­
CATION AND
DECODING DOCU­
MENTATION

Returned to sponsor to doc­
ument any decoding that may
have occurred

8.4.7 FINAL REPORT BY
INVESTIGATOR TO
IRB/IEC WHERE
REQUIRED, AND
WHERE APPLICA­
BLE, TO THE REGU­
LATORY AUTHORI­
TY^)

To document completion of
the trial

8.4.8 CLINICAL STUDY
REPORT

To document results and
interpretation of trial

60

Located in Files of
Investigator/
Sponsor
Institution

X

X

X
(if applicable)

X

Position: 1271 (4 views)