ICH Harmonised Tripartite Guideline for Good Clinical Practice
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ICH Harmonised Tripartite
Guideline for Good Clinical Practice
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f
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
- Media
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