Essential

Good Clinical
Practice
Professor David Hutchinson
© Professor David Hutchinson, 2017
Published by Canary Ltd, 5 Studley Court Mews, Chobham, Surrey, GU24 8EB, UK
Website: www.canarybooks.com
ISBN 978-1-912055-18-0
EAN 9781912055180
First edition, January 2009; Second edition, November 2017
All rights reserved. No part of this book may be reproduced, stored in a retrieval
system, or transmitted in any form or by any means, electronic, electrostatic,
magnetic tape, mechanical, photocopying, recording or otherwise, without prior
written permission of the publisher.
Artwork by: LIMA Graphics, Fleet, Hampshire, UK
Printed by: Surrey Litho, Great Bookham, Surrey, UK
Essential
Good Clinical
Practice
By Professor David Hutchinson
Contents
Page

Preface 1
Chapter 1: Introduction to good clinical practice 2
Factors affecting clinical trials 2
GCP development 5
Principles of GCP 10
Compliance with GCP 12
Documenting GCP compliance 13

Chapter 2: General GCP responsibilities and subject protection 14

The investigator and study site 14
Addressing the risks of trials 17
Management of investigational medicinal product 20
Product accountability 21
The study protocol 22
Recruiting trial subjects 24
Subject protection 25

Chapter 3: Study conduct and GCP compliance 30

Data collection in clinical trials 30
Safety monitoring, recording and reporting 34
Analysis and reporting of trial data 42
End of study procedures 43
GCP compliance and inspections 45
Due diligence is the key 46

Chapter 4: Essential study documentation 47

Computerized systems 48
Checklists of trial documents 50

Chapter 5: The sponsors’ quality management system 55

Risk-based approach to trial monitoring 57

Quiz 62

Answers to quiz 70
 Essential Good Clinical Practice

Preface
Good clinical practice (GCP) is an international quality standard. In order for
clinical trials on medicinal products in humans to achieve international recognition,
they should be conducted in accordance with GCP. In many countries this is a
legal requirement, as GCP principles have been incorporated into national laws.
Adherence to GCP is also a requirement for publication in many international
medical journals. Any reputable clinical trial should therefore be compliant with GCP.
This book is based on the GCP guidelines developed by The International Council
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(ICH GCP E6(R2)). The guidelines (ICH GCP) have become a proven international
standard that is globally recognized and is the guidance of choice for both
commercial and non-commercial trials. The ICH GCP requirements mainly affect the
development of new medicinal products. The principles can, however, be applied
to studies involving marketed products, other healthcare products such as herbal
and consumer medicines, and trials on nutritional products. Different standards
apply to studies involving medical devices.
The book is a revision of the 2009 edition and takes into account the latest GCP
changes. It aims to provide practical guidance and information about some of the
most important GCP responsibilities of sponsors and investigators. It looks at the
development of GCP; provides an overview of the principles of GCP; and examines
in more detail the GCP requirements relating to ethics, subject consent, protocol
compliance, data collection, safety reporting, managing the investigational product,
documentation, trial oversight and quality management.
This book is an ideal companion for those setting up trials (the sponsors) and those
performing trials (the investigators). It is also suitable for those who regulate trials,
such as members of ethics committees.
I hope that you enjoy it and find it useful.

Professor David Hutchinson

1
CHAPTER 1 Essential Good Clinical Practice

Introduction to good
clinical practice
Factors affecting clinical trials
Everyone involved in clinical trials in design and undertake trials as they
humans has a responsibility to ensure wished. A few voluntary codes existed.
that the trials are conducted to the
Today, human clinical research is
highest possible standards.
heavily regulated. A quality standard
Around 35 years ago there were called good clinical practice
few rules and regulations (GCP) should be followed in
affecting clinical trial all trials, wherever they are
conduct. Most sponsors and conducted.
investigators were free to

2
Introduction to good clinical practice
Declaration of Helsinki
The most notable code of practice that
underpins medical research in humans
is the Declaration of Helsinki. It is a set
of ethical principles established by the
World Medical Association (WMA).
It has been modified on many
occasions since it was first
published in 1964, following
a General Assembly of the
WMA in Helsinki (hence its
name).
The Declaration of Helsinki
provides protection for subjects
who take part in trials. It ensures
that subjects are provided with
information on the risks and benefits
3
of participation; requires informed
consent to be obtained; prohibits
coercion by investigators; and allows
subjects to withdraw from the trial at
any time without detriment to their
future care.
There have been many
controversial aspects to the
Declaration of Helsinki, in
particular the use of placebo
(inactive substance) in trials
and the requirement to provide
the best proven treatment at
the end of a trial. The latest version
of the Declaration of Helsinki can be
obtained from the WMA website at
<www.wma.net>.
 Essential Good Clinical Practice

Other regulations and guidelines countries, there are many similar

A process called ICH (International
Council for Harmonisation) has
generated guidance documents
for virtually every stage of drug
development, from non-clinical
to human studies.
Within the European Union (EU)
framework – expanded to the
European Economic Area (EEA),
with the agreed involvement of
Norway, Iceland and Liechtenstein –
directives and regulations have been
developed to harmonize procedures
throughout Europe. These have
been incorporated into the national
laws of EEA Member States. Whilst
there has not been complete
harmonization between European
procedures, making pan-European
trials easier to perform.
The regulations in the USA – published
in the Federal Register and referred
to as the Code of Federal Regulations
(CFR) – affect most commercial
research because, more often than not,
trials performed globally will be used
to support marketing applications in
the USA.
There are also strict data protection
laws (affecting the transfer and
processing of trial subjects’ data).
Inspectors from the regulatory
authorities visit sponsors and
investigators to check that the laws
and regulations are being followed.

REMEMBER:
In Europe, directives must be passed into Member States’ laws
within a specified time, but may be ‘gold plated’ to add additional
requirements within that country. Regulations are binding for all
EU Member States.
Europe accounts for about one-third of patients recruited into clinical
trials submitted as part of marketing authorizations. Another third
of the data are generated in the USA, leaving a large proportion
generated outside Europe and North America. For maximum
credibility, these trials should be performed in accordance with
internationally recognized GCP.

4
Introduction to good clinical practice
GCP development
What is GCP?
GCP is a quality standard. It applies to
every step of a clinical trial: from its
planning and design through to the
reporting of results.
GCP can be defined as follows:
“A standard for the design, conduct,
performance, monitoring, auditing,
recording, analyses, and reporting of
clinical trials that provides assurance
that the data and reported results are
credible and accurate, and that the
rights, integrity and confidentiality of
the subjects are protected” (ICH GCP
guidelines, Section 1.24).
From this we can summarize that
GCP requires
• procedures to be implemented to
help ensure that the participants
of studies – the trial subjects – are
fully protected; the subjects can be
healthy volunteers or patients
• procedures to be carried out so
that the data collected are accurate
and reliable.
5
Who does GCP affect?
Everyone involved in a clinical trial
has a duty to ensure that the trial is
performed properly and to the highest
possible standards. Therefore, GCP
affects everyone who is involved in
a clinical trial.
Responsibilities are defined in the GCP
guidelines for
• trial sponsors – those that organize,
manage and fund clinical trials, such
as pharmaceutical companies (and
other commercial organizations) and
non-commercial organizations
• investigators – physicians or
dentists and members of their study
teams, such as other doctors, nurses
and administrators
• ethics committees.

Where did GCP start?
Specific requirements for doctors/
investigators performing human
clinical trials were first introduced in
the USA in the late 1970s. This set
the standard for research. The US
regulatory authorities then deemed
research conducted outside the USA to
be less acceptable. This often meant
that trials that had not been performed
within the USA had to be repeated
to US standards, before they would
be accepted as part of a marketing
authorization application. This costly
and time-consuming duplication of
research quickly led to other countries
introducing guidelines to improve the
quality and acceptability of their own
clinical trials.
6
Essential Good Clinical Practice
European GCP
A period of time then ensued where
individual countries developed
their own GCP guidelines. This was
followed in 1990 by the adoption of
a harmonized set of European GCP
guidelines. These guidelines then had
to be implemented into the national
laws of the EU Member States. Some
Member States achieved this by 1992.
By 1996, GCP had finally become a
legal requirement in all EU Member
States. Despite this, studies performed
in one country were not always
acceptable in another country.
Harmonization of procedures
The EU prompted a meeting to discuss
the wider harmonization of drug
development procedures, so that
one method would be acceptable
to all. The first ICH conference took
place in Brussels in April 1990. The
unique meeting brought together
representatives from the world’s
most active pharmaceutical research
and development regions. It involved
the regulatory authorities and
pharmaceutical industry associations
from Europe, Japan and the USA.
Introduction to good clinical practice

The conference has since developed The ICH ‘family’ is now truly global and
into an effective and highly successful representatives of many organizations
process to provide guidance on all have membership of ICH. A list of the
aspects of drug development, known current members is available on the
simply as ICH. The ICH website ICH website.
contains a great deal of useful
The ICH process has produced a great
information about the process,
deal of useful guidance covering all
including its products and plans for
aspects of drug development. This
the future (see <www.ich.org>).
includes guidance relating to the
The ICH Management Committee is quality of medicines (the ‘Q’ guidelines),
made up of the six original members guidance on non-clinical safety studies
(regulators and pharmaceutical (the ‘S’ guidelines), guidance on studies
industry representatives) as well in humans (the ‘E’ guidelines) and
as Health Canada, Swissmedic, the guidance on miscellaneous topics
World Health Organization (WHO) (the ‘M’ guidelines). The E guidelines
and the International Federation of are the most important products for
Pharmaceutical Manufacturers and human clinical trials. A summary of
Associations (IFPMA). The original the ICH products in the E section is
pioneers of the ICH process were: provided overleaf.
• regulators: European Commission
(EU); Japanese Ministry of
Health, Labour and Welfare
(MHLW/PDMA); and the US Food
and Drug Administration (FDA)
• pharmaceutical industry
representatives: European
Federation of Pharmaceutical
Industries and Associations
(EFPIA); Japan Pharmaceutical
Manufacturers Association (JPMA);
and Pharmaceutical Research and
Manufacturers of America (PhRMA).

7

SUMMARY OF
ICH PRODUCTS:
E1: Extent of population exposure to assess
safety
E2: Safety reporting (in parts E2A, B, C, D,
E and F)
E3: Clinical study reports
E4: Dose response information to support
registration
E5: Ethnic considerations
E6: GCP guidelines
E7: Clinical trials in special populations –
geriatrics
E8: General considerations
E9: Statistical principles
E10: Choice of control group
E11: Studies in children
E12: Therapeutic area guidelines
E14: Clinical evaluation for anti-arrhythmic
drugs
E15, E16, E18: Genomics topics
E17: Multi-regional clinical trials
E19: Safety data collection
The list of ICH products is always increasing
and existing guidelines are regularly being
revised. For the most up-to-date information,
the ICH website <www.ich.org> should be
regularly checked.
8
Essential Good Clinical Practice
ICH GCP guidelines
One of the most important
ICH products is the ICH GCP
guidelines. The guidelines have
become the internationally
accepted way in which to
undertake clinical trials and their
principles have been incorporated
into the national laws of many
countries. By following the ICH
GCP guidelines, clinical trials will
be accepted by the regulatory
authorities of all European
countries, and in the USA, Japan,
Canada, Switzerland and many
other countries.
The ICH GCP guidelines are
divided into eight sections:
1. Glossary of terms (definitions)
2. Principles of GCP
3. Institutional review board/
independent ethics committee
4. Investigator
5. Sponsor
6. Clinical trial protocol and
amendments
7. Investigator’s Brochure
8. Essential documents.
Introduction to good clinical practice
The ICH GCP requirements broadly
focus on three main areas: subject
protection, the reliability and integrity
of data, and documentation.
Subject protection
All trials have to be performed in
accordance with a set of ethical
principles laid down in the Declaration
of Helsinki. The risks of participation
in a trial should be carefully evaluated
and documented in a formal risk
assessment. Risks should be
outweighed by the benefits to the
subject. The informed consent of
trial subjects should be obtained.
A favourable ethics committee
opinion is required before the study
commences. Any decisions about
the subjects’ medical care should be
made by a doctor.
9
Data quality
Requirements include the careful and
diligent collection of data, accurate
record form completion, frequent
monitoring of the trial and a series
of quality checks to ensure that all
recorded data are reliable.
Good documentation
GCP encourages good documentation
practices. Every step of the trial has
to be documented to prove GCP
compliance. These factors all help
to improve the quality of trials and
this helps regulators to make reliable
decisions when considering marketing
applications.

Principles of GCP
Following the principles of GCP is a
legal requirement in most countries.
In some countries, such as the UK, the
wording in the ICH GCP guidelines has
been slightly amended but the spirit of
the principles remains the same. The
thirteen principles of ICH GCP are listed
below (reproduced from Section 2 of
the ICH GCP guidelines).
• Clinical trials should be conducted
in accordance with the ethical
principles that have their origin in
the Declaration of Helsinki, and that
are consistent with GCP and the
applicable regulatory requirement(s).
10
Essential Good Clinical Practice
• Before a trial is initiated, foreseeable
risks and inconveniences should be
weighed against the anticipated
benefit for the individual trial
subject and society. A trial should be
initiated and continued only if the
anticipated benefits justify the risks.
• The rights, safety, and well-being
of the trial subjects are the most
important considerations and should
prevail over interests of science and
society.
• The available nonclinical and clinical
information on an investigational
product should be adequate to
support the proposed clinical trial.
• Clinical trials should be scientifically
sound, and described in a clear,
detailed protocol.
• 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.
Introduction to good clinical practice

• The medical care given to, and

medical decisions made on behalf
of, subjects should always be the
responsibility of a qualified physician
or, when appropriate, of a qualified
dentist.
• Each individual involved in
conducting a trial should be
qualified by education, training,
and experience to perform his or
her respective task(s).
• Freely given informed consent
should be obtained from every
subject prior to clinical trial
participation.
• All clinical trial information should
be recorded, handled, and stored
in a way that allows its accurate
reporting, interpretation and
verification. This principle applies
to all records referenced in this
guideline, irrespective of the type
of media used.
• The confidentiality of records that
could identify subjects should be
protected, respecting the privacy and
confidentiality rules in accordance
with the applicable regulatory
requirement(s).
• 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.
• Systems with procedures that
assure the quality of every aspect
of the trial should be implemented.
Aspects of the trial that are essential
to ensure human subject protection
and reliability of trial results should
be the focus of such systems.

11

Compliance with GCP
For a trial to be globally acceptable
to regulatory authorities, it is essential
for sponsors and investigators
performing both commercial and
non-commercial trials to
comply with the principles
of GCP. The national laws
of many countries require
this. In addition, the
major medical journals
will not accept studies for
publication if they have not been
performed in accordance with GCP.
Inspections are undertaken by the
regulatory authorities to check GCP
compliance. Failure to comply may
lead to sanctions being imposed on the
sponsor and/or investigator.
Furthermore, for the consideration of
a study for publication in many of the
major medical journals, the editors
require a declaration by the authors
that the study has been performed to
GCP standards.
12
Essential Good Clinical Practice
Organisations are able to ensure
that their staff comply with GCP
requirements by establishing a set
of Standard Operating Procedure
(SOPs). These should describe
every procedure undertaken
in a clinical trial. SOPs are
relevant for sponsors,
investigators and ethics
committees. They should
form the working manual for
those who have to undertake
the procedures, and should provide
details of exactly how a procedure
must be performed and documented.
SOPs should be regularly reviewed and
updated.
GCP protects subjects and facilitates
the collection of reliable data – it is an
important quality standard.
Introduction to good clinical practice

Documenting GCP compliance

Both sponsors and investigators
need to demonstrate that they have
complied with GCP, their SOPs and all
legal requirements. Documenting
every step of the trial is one way
to demonstrate this.
Documents are generated
before, during and after
a trial. They are called
essential documents. Essential
documents may be paper-
based or may be electronic records.
As the trial progresses, the essential
documents are collected together in
a study file. There will be a study file
at both the investigator and sponsor
sites. At the sponsor site, the study file
is called the Trial Master File (TMF). The
TMF may be totally paper, completely
electronic or it may be a mixture of both
paper and electronic records. Whatever
the system used, the TMF must be
carefully defined and a log maintained
of the documents kept within it, and
their location. All documents stored in
the TMF must be quickly retrievable
and readily available for audit
and inspection.
Many of the documents are
common to both study files.
However, some are exclusive
to either the sponsor or the
investigator site. For example,
documents that identify trial subjects
are unique to the investigator site. The
original copies of documents that do
not identify subjects are usually kept
in the sponsor’s TMF.
Someone should be appointed to
manage the study files. To ensure that
documents are not lost or damaged,
access to the study files must be
restricted.

REMEMBER:
If it is not documented, it didn’t happen!
The minimum content of the study file at both the sponsor
and investigator sites is listed in Section 8 of the ICH
GCP guidelines. This is not a definitive list and there are
many other documents that make up the TMF. The TMF
documents list is trial-specific.
13
CHAPTER 2 Essential Good Clinical Practice

General GCP responsibilities

and subject protection
The investigator and study site
The success of any clinical trial is
down to the selection of a suitable
investigator and study site personnel.
They must be appropriately qualified,
trained and have the experience and
expertise to undertake the trial. The
sponsor must carefully consider the
personal and professional qualities
of the investigator. GCP requires the
sponsor to undertake a thorough site
assessment to ensure that both the
investigator and the proposed trial site
are suitable.
It is usual for the principal investigator
– ie. the person who is responsible for
the overall conduct of the trial – to
delegate duties to other members
of the study team. However, it is
important that members of the study
team only perform the duties delegated
to them. They must be legally allowed
to undertake those duties, which
must be within their experience and
capabilities. The sponsor must check
compliance with this requirement.

REMEMBER:
The investigator must have time to undertake the study,
sufficient potential trial subjects, and suitable facilities and
supporting staff.
14
General GCP responsibilities and subject protection
Before they take part in a study, all
staff should be properly trained and
briefed. They should be aware of and
should follow the study protocol, and
should know about the medicines
being used in the trial.
The investigator plays a central part in
a hub of trial activities and processes.
Log of study personnel
It is important for investigators to keep
a log of the site personnel involved in
the study. This log should document
who was involved, their qualifications,
when they were involved (start and end
dates/times, depending on the nature
of the study) and what their trial-
related duties were.
15
In order to demonstrate that a
person involved in a trial is suitably
experienced and has the qualifications
required, an up-to-date signed and
dated curriculum vitae (CV) should be
provided by that person. This should
be kept on file and updated when
appropriate. CVs are particularly
important for team members who
have significant trial-related duties,
such as obtaining the consent of
subjects, undertaking assessments and
completing record forms. CVs might not
be required for personnel with minor,
supervised roles; however, if in doubt
a CV should be kept on file.
 Essential Good Clinical Practice

Oversight of the trial

The investigator is responsible for
supervising any individual or party
who is delegated trial-related
duties and functions. For example,
the delegation of the consent
process to a subinvestigator, the
involvement of a trial pharmacist
to dispense trial medication or the
collection of data by a study nurse
all require appropriate oversight. The
investigator should
• ensure that the person or party is
qualified and experienced enough
to do the task
• make sure the person is named,
and their qualifications and
experience are documented
Equipment requirements
• check that the person is
The study site must have the relevant
performing the duty or function
equipment and facilities in order to
correctly – and document how
perform the trial. Equipment used
they have done this.
in a trial must be suitable, properly
maintained and calibrated; records should
be available to confirm this. For example,
a refrigerator used to store trial samples
should have a temperature alarm in case
of failure; its temperature and condition
should be regularly checked by study
staff (signing a log of activity); and the
refrigerator should ideally be dedicated
to the trial to avoid cross-contamination.
The equipment and facilities must be
available to the trial when required.

16
General GCP responsibilities and subject protection
Addressing the risks of trials
Clinical trials in humans can carry a
significant risk for those who take
part. This was plainly obvious when
a first-in-man (Phase I) clinical trial in
eight healthy volunteers went wrong
in March 2006. Six of the subjects
who were taking part were given a
single dose of a biological product (a
monoclonal antibody), and suffered
immediate and unexpected life-
threatening side-effects. The other two
subjects taking placebo witnessed the
dreadful events but were unharmed
themselves. Events such as this lead
to the review of trial regulations.
Another ‘first-in-human’
study in France in 2016
also ended in tragedy,
and this too led to new
guidelines being issued on
the conduct of clinical trials
in humans being given a new
medicine for the first time.
The risks of all clinical trials, in any
phase of a product’s development,
should be carefully evaluated by the
sponsor and investigator, and plans
put into place to identify, evaluate
and control risks to both trial subjects
and the data being collected. Plans
should be in place to deal with any
unforeseen event.
17
Disasters in trials are rare. However, all
members of the study team should be
aware of what to do in an emergency
situation (eg. following accidental
overdose or the emergence of sudden
and serious side-effects).
Indemnity
European legislation implemented
into national laws makes it a legal
requirement that sponsors of trials
have insurance that indemnifies the
investigator, as well as providing
compensation to trial subjects, in the
event of trial-related injuries.
The investigator would not usually
be indemnified in the event of
his/her own negligence (eg.
normal medical procedures
going wrong, and perhaps
failure to comply with the
protocol requirements). However,
indemnity would be provided to cover
investigators in the event of trial-
and product-related damages.
It is important that an adequate
amount of insurance cover is provided
by the sponsor to cover damages,
particularly for a number of subjects
suffering problems in the same trial;
this amount should be checked by
the investigator.

Compensation
Procedures should be in place to
compensate subjects in the event of
trial-related injuries. Subjects should
be informed that compensation is
available and details provided on
how to obtain it. The discussion of
compensation with potential subjects
is clearly a sensitive issue and
needs to be managed openly
but carefully.
Before embarking on a trial,
the investigator should
ensure that these protections
are in place and that
agreements with the sponsor
have been signed.
Both indemnity and compensation
arrangements are likely to be reviewed
by the ethics committee when an
application for an opinion is made.
18
Essential Good Clinical Practice
Both non-commercial research
institutions and pharmaceutical
companies usually take out insurance
policies to cover claims arising from
clinical trials. The limit of indemnity
covered by the insurance is variable,
and many policies have conditions
attached.
Numerous pharmaceutical
companies and their
investigator sites agree to
use standard clinical trial
compensation guidelines,
such as those published
by the Association of the
British Pharmaceutical Industry
(ABPI). The ABPI guidelines provide
a simple and expeditious procedure
for the provision of compensation
for injury caused by participation in a
clinical trial. The guidelines form part
of commonly used model clinical trial
agreements. Some basic principles for
compensation (based on some of the
ABPI principles) are given below.
General GCP responsibilities and subject protection

Compensation should be paid

• regardless of whether the patient is able to prove that the company has been
negligent in relation to research or development of the medicinal product
under trial
• when, on the balance of probabilities, the injury was attributable to the
administration of a medicinal product under trial, or any clinical intervention
or procedure provided for by the protocol that would not have occurred but
for the inclusion of the patient in the trial
• for more serious injury of an enduring and disabling character, and not for
temporary pain or discomfort or less serious or curable complaints.

Even if an adverse reaction causing the part in the trial – this should not
injury was foreseeable or predictable exclude a patient from consideration
– and regardless of the fact that the for compensation.
patient has freely consented to take

19
 Essential Good Clinical Practice

Management of investigational medicinal

product
Information and knowledge
When a clinical trial involves the
administration of a medicinal product,
it is important that all members of
staff are familiar with the correct and
appropriate use of that medicine.
Information on the trial’s
investigational medicinal
products (IMPs) will be
provided by the sponsor in
the form of an Investigator’s
Brochure. This concise, ‘state-
of-the-art’ document should be
read by the investigator and made
available to those who need to refer
to it. The Investigator’s Brochure is a
compilation of non-clinical and clinical
knowledge on the IMP. It should be
updated by the sponsor at least once
every year.
The Investigator’s Brochure forms
part of the documentation that allows
the investigator to evaluate the risks
and benefits of the trial, when
deciding whether or not to
participate. The Investigator’s
Brochure is also useful
when determining whether
observed untoward effects
are related to the IMP.
If the product is already marketed,
information about the medicine can
be found in its Summary of Product
Characteristics. This is an approved
data sheet.

REMEMBER:
The information in the Investigator’s Brochure should be
presented in a concise, simple, objective, balanced and non-
promotional form.
20
General GCP responsibilities and subject protection
Product accountability
An important GCP responsibility at
the investigator site is to ensure that
IMPs are only used to treat subjects
in the trial. Every single dose of study
medication has to be accounted for in
written documentation. This is
called product accountability.
Records include
• how much product has
been received from the
sponsor, and when
• what has been dispensed to
the trial subjects, and when
• what is returned unused by the
subject (and this should reconcile
with what is in stock)
• what is returned to the sponsor,
and when.
Unused medicines are usually returned
to the sponsor for reconciliation and
destruction.
21
IMPs should be stored securely in
suitable conditions, with access by
authorized persons only. Ideally, trial
medications should be stored in a
pharmacy, under the supervision of
a nominated trial pharmacist.
The trial materials should be
kept in a separate area of the
pharmacy (quarantined).
Sponsors should have
detailed records of the IMP
manufactured, compliance
with Good Manufacturing Practice,
expiry dates, and what has been
supplied to and retrieved from the
investigator site.
Product accountability records aid
compliance evaluations to determine if
the trial subjects have taken their trial
medication as required.

The study protocol
One of the most important documents
relating to the trial is the study
protocol. This is usually prepared by
the trial sponsor. It describes all the
procedures that have to be followed
by the investigator.
The content of the protocol includes
• the aims of the study
• which subjects are to be
recruited, using inclusion
and exclusion criteria
• how and when the
medicines are to be
administered
• how and when evaluations are to be
performed
• what to do if adverse events occur
• how all study data will be collected
and analysed.
Protocols may vary in structure and
format between different sponsors,
but their content will essentially be
the same. They should be prepared in
accordance with SOPs and Section 6
of the ICH GCP guidelines (Section 6
contains more information on clinical
trial protocols).
22
Essential Good Clinical Practice
Compliance with the study protocol
is essential. Violations of any aspect
of the protocol are unwelcome.
The quality of the trial – and the
performance of the site – will be
measured against the number and
nature of any protocol violations.
Everyone involved in the trial
should be familiar with the
protocol and should follow it.
They should ensure that they
are working with the current
version that includes any
amendments.
Appropriate study site staff must
know where the protocol is kept and
must have access to it. They must refer
to it at all times.
In the undesirable event that a protocol
violation occurs (eg. if an assessment
is not undertaken at the right time), it
must be documented and brought to
the attention of the sponsor. Mistakes
do happen in trials, but they must not
be concealed.
General GCP responsibilities and subject protection

Finally, it is not acceptable for In Europe, procedures for the approval

a sponsor of a trial to allow an of substantial amendments or
investigator to enter subjects who do modifications are documented in
not strictly fulfil the entry criteria, or national law. These involve notification
to permit any other deviation from the of both the competent (regulatory)
protocol using waivers. Waivers breach authority and the ethics committee.
ethics and regulatory approval, and The sponsor will help investigators to
may have serious implications for the comply with this process.
statistical integrity of the study.
In the event of an emergency involving
Protocol amendments an immediate hazard, it is possible
It is possible to amend a protocol to amend the protocol to protect trial
during a trial. However, there are strict subjects at risk. However, the correct
procedures for doing this and ad hoc process of informing the sponsor
changes must not be implemented and ethics committee must then
without the proper approvals. be followed.
A protocol amendment must be
agreed by the sponsor and investigator.
Unless it is of a very administrative
nature, it should then be submitted
to the appropriate ethics committee
for evaluation. The amendment
may not be implemented until the
favourable opinion/approval of the
ethics committee has been obtained
in writing.

23

Recruiting trial subjects
The investigator needs to evaluate the
potential recruitment of trial subjects.
This estimate should be based on the
throughput of subjects who are likely to
meet the study entry criteria described
in the study protocol. A common error is
for investigators to base their estimates
on the total number of subjects with
the particular condition being studied,
forgetting that as many as 50–60%
may have to be excluded from the study.
The investigator site needs to keep a
record of who is screened for entry to
the study – this demonstrates that
proper selection is being undertaken
based on the protocol – and who is
actually entered into the study.
24
Essential Good Clinical Practice
Subject screening or enrolment log
Information about subjects who have
been screened and entered into the
trial should be recorded in the subject
screening log or the subject enrolment
log. This records subjects’ names
and their unique study numbers. It
may also include their dates of birth,
health service numbers and dates
of participation in the trial. Only the
investigational site keeps a record of
the subjects’ identities.
The subject enrolment log is an
important document, as it is unique to
the study site and is the main way in
which a subject can be identified later.
General GCP responsibilities and subject protection
Subject protection
Ethics committee opinion
The favourable opinion (‘approval’) of
an independent ethics committee (IEC)
(or institutional review board (IRB) as
they are called in some countries)
is required before the trial can
begin. IECs/IRBs are made up
of medical and non-medical
members. It is their job to
ensure that the rights, safety
and well-being of the trial
subjects are protected.
To obtain an opinion, a comprehensive
package of documents and information
has to be submitted to the IEC/IRB. In
some regions, a standard application
form is used. The IEC/IRB will then
review the application and provide its
opinion. In Europe, strict timelines are
placed on the ethical review of clinical
trials. A new Regulation in Europe to
be implemented in 2019 will require
an electronic application to obtain a
single combined regulatory and ethics
approval. In other regions there may be
no timeline established and obtaining
an ethics committee opinion may be a
significant rate-limiting step.
25
Some of the submitted documents
need to be approved by the
IEC/IRB, whilst others are submitted
to help the IEC/IRB make its decision.
The documents needing specific
approval are
• the final version of the
study protocol and any
subsequent amendments
• the documentation used
to provide information to and
obtain the consent of the subject
(and any updates), eg. subject
information sheets and consent
forms
• the materials used to recruit study
subjects, such as advertisements
and posters.
The IEC/IRB should review its opinion/
approval annually. Sponsors and
investigators should ensure that
this occurs.
 Essential Good Clinical Practice

Consent procedures document, but should be presented

Freely given written informed consent in a simple, plain-language format.
is required before any subject
Subjects should be given ample time to
enters the trial and any trial-related
decide about the trial. They must not
assessments are undertaken (including
be coerced into participation. They are
those that would usually be conducted
always free to withdraw from the
as part of normal clinical practice:
study at any time, even though
if the data are recorded for
they initially gave consent to
the trial, they are considered
participate. It is good practice
trial-related!).
to check that the subject
Each prospective subject understands the information
must be provided with before he/she signs the
information verbally and in consent form.
writing using an approved subject
When subjects cannot consent for
information sheet. In some countries
themselves (eg. children), are unable
(eg. the USA), the document may need
to read or write, or are mentally
to bear the stamp of the approving
impaired, special consent procedures
ethics committee.
exist. These are laid down in national
ICH GCP Section 4.8.10 requires the law. In these cases a witness or a legal
information sheet to contain 20 items representative may be required.
of information. The subject information
sheet tends to be quite a long

26
General GCP responsibilities and subject protection
Information to be provided
The items of information to be
presented to trial subjects are stated
in the ICH GCP guidelines (Section
4.8.10), and reproduced below:
(a) That the trial involves research.
(b) The purpose of the trial.
(c) The trial treatment(s) and the
probability for random assignment
to each treatment.
(d) The trial procedures to be followed,
including all invasive procedures.
(e) The subject’s responsibilities.
(f) Those aspects of the trial that
are experimental.
(g) The reasonably foreseeable risks or
inconveniences to the subject and,
when applicable, to an embryo,
fetus, or nursing infant.
27
(h) The reasonably expected benefits.
When there is no intended clinical
benefit to the subject, the subject
should be made aware of this.
(i) The alternative procedure(s) or
course(s) of treatment that may
be available to the subject, and
their important potential benefits
and risks.
(j) The compensation and/or
treatment available to the subject
in the event of trial-related injury.
(k) The anticipated prorated
payment, if any, to the subject
for participating in the trial.
(l) The anticipated expenses, if any,
to the subject for participating
in the trial.
(m) That the subject’s participation in
the trial is voluntary and that the
subject may refuse to participate
or withdraw from the trial, at any
time, without penalty or loss of
benefits to which the subject is
otherwise entitled.

(n) That the monitor(s), the auditor(s),
the IRB/IEC, and the regulatory
authority(ies) will be granted direct
access to the subject’s original
medical records for verification
of clinical trial procedures and/
or data, without violating
the confidentiality of
the subject, to the
extent permitted by the
applicable laws and
regulations and that, by
signing a written informed
consent form, the subject or
the subject’s legally acceptable
representative is authorizing such
access.
28
Essential Good Clinical Practice
(o) That records identifying the subject
will be kept confidential and, to the
extent permitted by the applicable
laws and/or regulations, will not
be made publicly available. If the
results of the trial are published,
the subject’s identity will remain
confidential.
(p) That the subject or the
subject’s legally acceptable
representative will be
informed in a timely manner if
information becomes available
that may be relevant to the
subject’s willingness to continue
participation in the trial.
(q) The person(s) to contact for further
information regarding the trial and
the rights of trial subjects, and
whom to contact in the event of
trial related injury.
(r) The foreseeable circumstances
and/or reasons under which the
subject’s participation in the trial
may be terminated.
(s) The expected duration of the
subject’s participation in the trial.
(t) The approximate number of
subjects involved in the trial.
General GCP responsibilities and subject protection
Other parts of the GCP guidelines
have consent implications, such as
Section 4.3.3 which recommends that
a subject’s primary care physician
is informed about the subject’s
participation in the trial.
The process of obtaining
properly informed consent
is a serious matter. It is
not easy to ensure that all
the information is provided
verbally. Investigators may
choose to use the subject
information sheet as a prompt.
A key item to note from the list is the
provision of information in a balanced
way about the risks, inconveniences
and benefits of participation. Data
protection laws also affect the content
of consent forms, and subjects should
consent to their personal data being
processed and transferred.
Signing consent forms
When consent is obtained, the subject
signs and dates the consent form.
In addition, the person obtaining
consent must also sign and date
the form, together with any witness
when required. It is not acceptable
for the investigator to date the
subject’s consent.
29
In some cases, the investigator may
delegate the consent process to an
appropriate member of his/her study
team. However, as with all delegated
trial obligations, the investigator
retains overall responsibility for the
consent process and should
ensure that it is undertaken
in accordance with GCP and
any relevant national laws.
Updates to consent forms
If information becomes
available during the course of
a clinical trial that might affect the
subject’s willingness to participate
– for example if a large number of
serious adverse reactions become
evident – the consent form should
be updated and the subject informed
of the new information. It might be
necessary in these cases to suspend
subject recruitment until the ethics
committee has reviewed and approved
the use of the updated information
sheet and consent form. The sponsor
should advise the investigator on how
best to proceed in these circumstances.
CHAPTER 3
Study conduct and GCP
compliance
Data collection in clinical trials
Data collected in a clinical trial
are recorded in a subject-specific
document called a case report form
(CRF). The CRF identifies the subject
using a unique study number. The
subject’s initials and date of birth
may be collected, but to preserve
confidentiality subjects’ names should
never be recorded in the CRF or in any
other document that will leave the
study site (eg. laboratory reports).
There are some basic rules for the
collection of data in clinical trials.
These are referred to in ICH GCP as
the ALCOA-C principles, whereby all
data should be attributable, legible,
contemporaneous, original, accurate
and complete:
REMEMBER:
Investigators should make sure that they clearly record
a subject’s participation in a trial in their medical records
(patient files).
30
Essential Good Clinical Practice
• attributable – showing who
undertook the observation and
recorded it
• legible – clear and readable
• contemporaneous – recorded at the
same time the observation is made
• original – be careful where data are
recorded for the first time; copies of
data are not acceptable unless they
have been checked and certified
• accurate – diligent observations
should be made and recorded
correctly
• complete – missing data should
be avoided, and source documents
should be complete and record all
data generated.
Study conduct and GCP compliance
This means that:
• CRFs must be completed accurately,
fully and legibly
• data should be collected and entered
in the CRF within the right timescale
• the data should be attributable to
a particular subject
• missing data must be avoided
• Source data. All information in
• it should be possible to identify
who collected and then entered
the data in a CRF.
The original pages from CRFs are
usually collected by the sponsor as
the trial progresses. This enables the
data to be checked and entered into
the trial database in a timely manner.
The investigator should retain a copy of
• Source documents. Original
the data (eg. a copy of the CRF pages).
Source documents
Maintaining source documents
to support the data recorded
in trial-specific CRFs is a key
GCP requirement. Data in
documents should be detailed
enough to allow the trial to be
reconstructed from investigator-
site documents. The location of
the source documents should be
documented.
Source data and source documents are
defined by ICH GCP (Sections 1.51 and
1.52, respectively) as follows.
31
REMEMBER:
Source documents are
the original documents,
data and records –
effectively the first
practicable place where
data are recorded.
original records and certified copies
of original records of clinical findings,
observations, or other activities
in a clinical trial necessary for the
reconstruction and evaluation of the
trial. Source data are contained in
source documents (original records
or certified copies).
documents, data and records (eg.
hospital records, clinical and
office charts, laboratory notes,
memoranda, subjects’ diaries
or evaluation checklists,
pharmacy dispensing
records, recorded data from
automated instruments, copies
or transcriptions certified after
verification as being accurate copies,
microfiches, photographic negatives,
microfilm or magnetic media, X-rays,
subject files, and records kept at the
pharmacy, at the laboratories and
at medico-technical departments
involved in the clinical trial).

The subject’s medical record (or patient
file) is often the source document.
In addition, laboratory result sheets,
recordings from an automated
instrument like an ECG and a subject’s
bedside chart – and even making an
informal note of a blood pressure
on a scrap of paper – are also
source documents.
Sometimes the CRF is used
to record data directly. It
then becomes the source
document. The protocol should
identify any source data that
will be recorded directly into the CRF.
However, auditors and inspectors much
prefer that the source document is
something other than the CRF, so that
data can be recreated if the CRF pages
are lost or damaged.
REMEMBER:
To minimize further effort,
investigators should
ensure that any data
recorded in CRFs match
those in original source
documents.
32
Essential Good Clinical Practice
When recording data, investigators
should think carefully before they
write the result down. The place they
write it becomes the source document,
and it is this document that study
monitors, auditors and inspectors
will wish to see.
If investigators need to change
source data in their own
records, the original entry
should not be obscured; if
it is unclear why the change
has been made, this should
be explained.
Monitoring and source data
verification
It is a GCP requirement that sponsor’s
monitors visit the investigator site
before, during and after the trial.
At one of the pre-study visits
the monitor will undertake a site
assessment. Once a site is selected, the
monitor will then brief the study team
about the trial. This will be extensive
as every aspect of the protocol, subject
recruitment, data collection and IMP
management will be discussed.
The monitor will visit the study site
regularly during the trial. He/she
will check on trial progress and will
identify any areas of concern that the
investigator team may have. Another
important role of the monitor is to look
at the data recorded in the CRFs.
Study conduct and GCP compliance

The monitor will also compare the Regulatory Agency) in writing, within
source documents with the data in 7 days of discovery.
the CRFs. This process is called source
When significant non-compliance
data verification. The monitor will need
with the protocol or GCP is identified,
a period of ‘quiet time’ during his/her
the sponsor should perform a root
visit to undertake this process. The
cause analysis and implement, and
investigator will be asked to explain
document, appropriate corrective and
and resolve any discrepancies between
preventative actions.
the source data and the data recorded
in the CRF. Correcting data in CRFs
If a change is required to data
Breaches of protocol and GCP
already recorded in a CRF, there is a
If a member of the sponsor or
very precise way in which this must
investigator team becomes aware
be undertaken. The sponsor’s trial
of a breach of GCP or a violation
monitors will ensure that this process
of the study protocol, they should
has been properly followed and will
immediately report this to their
require remedies to be made if it
supervisor or the principal investigator.
has not.
The violation should usually be
In order to change data already
documented in the trial file, stating
recorded in a CRF, the investigator
what the violation was, how
simply crosses through the
it was corrected and what
incorrect data with a single
steps were put into place to
line, writes the new data
prevent its recurrence. If an
alongside, and initials
inspection is undertaken by
and dates the change.
the regulatory authorities, the
For example:
inspectors may ask for a list of
protocol violations.
A special situation exists in the UK,
where it is a legal requirement for
sponsors to report serious breaches
4
DRH 15/9/17
of GCP and serious protocol violations
to the UK regulatory authority (the
Medicines and Healthcare products

33
 Essential Good Clinical Practice

Where the reason for the change is
not obvious it will need to be added,
for example if data are changed a long
time after they were initially recorded.
Correcting fluids should not be used to
hide a previous piece of data.
This process should also be followed by
investigators when there is a need to
change critical efficacy or safety data in
their source documents.

WHY MONITOR?
The purpose of trial monitoring is to verify that
(a)the rights and well-being of human subjects are protected
(b)the reported trial data are accurate, complete and verifiable
from source documents
(c) the conduct of the trial is in compliance with the currently
approved protocol/amendment(s), with GCP and with the
applicable regulatory requirement(s).
(ICH GCP guidelines, Section 5.18.1)

Safety monitoring, recording and reporting

The process of safety monitoring,
recording and reporting is called
pharmacovigilance. There are strict
regulations that state how safety
information should be reported in
clinical trials.
The ICH E2 guidelines (see
<www.ich.org>) provide more detail
on the requirements for safety,
for example:
• E2A – Clinical Safety Data
Management: Definitions and
Standards for Expedited Reporting
• E2B – Clinical Safety Data
Management: Data Elements for
Transmission of Individual Case
Safety Reports (also E2B(M))
• E2C – Clinical Safety Data
Management: Periodic Safety
Update Reports for Marketed Drugs

34
Study conduct and GCP compliance
• Addendum to E2C: Periodic Safety
Update Reports for Marketed Drugs
• E2D – Post-Approval Safety Data
Management: Definitions and
Standards for Expedited Reporting
• E2E – Pharmacovigilance Planning
• E2F – Development Safety Update
Report.
ICH guideline E19 provides information
on safety data collection.
As part of the essential safety
monitoring process, investigators
should identify and record any
untoward medical events that occur
during the trial.
Adverse events
Investigators are asked to record all
adverse events in the CRF, even those
that are expected and unrelated to
treatment. The ICH GCP guidelines
(Section 1.2) define adverse events
as “Any untoward medical occurrence
in a patient or clinical investigation
REMEMBER:
The safety of subjects
in trials is the most
important consideration.
35
Commonly used safety
abbreviations
PV pharmacovigilance
AE adverse event
ADR adverse drug reaction
AR adverse reaction
SAE serious adverse event
SAR serious adverse reaction
SUSAR suspected unexpected
serious adverse reaction
PSUR periodic safety update
report
QPPV Pharmacovigilance
Qualified Person
subject administered a pharmaceutical
product and which does not necessarily
have a causal relationship with
this treatment”.
An adverse event can therefore be
any unfavourable and unintended
sign (including an abnormal laboratory
finding), symptom or disease
associated with the use of an IMP.
The italicized part of the above
definition is important: it should be
noted that an adverse event does not
necessarily have to be related to the
investigational product.
 Essential Good Clinical Practice

When recording an adverse event, • the investigator could ask the

investigators are usually asked to
determine and record
• details of the nature and timescale
of the event
• if it has a causal relationship with
study medication
• the subject could be asked leading
• the severity of any adverse event
• the outcome.
subject if they have had any
problems, using a ‘non-leading’
question such as, “How have
you been since your last visit?”
or “Has the treatment upset you
in any way?”
questions using an adverse events
checklist.

Adverse events should be followed In addition to general observation, the

up by the investigator until their
resolution, updating the CRF as
required.
There are a number of ways in which
investigators may obtain information
from subjects about adverse events:
• a trial subject could spontaneously
volunteer information during a visit
• the investigator could observe a sign
during the examination of a patient
most commonly used method to identify
adverse events is to ask the subject a
non-leading question. As different ways
of obtaining information about adverse
events give rise to different frequencies
in reporting, it is important that the
same method is used for each subject
in each trial. This aids the comparison of
adverse event profiles between studies.
The method to be used should be
described in the study protocol.

Examples of adverse events:

• an elderly patient falls in the street and fractures her wrist
• a child who is a known asthma sufferer has an attack soon after taking trial
medicine and is hospitalized for several days
• a patient suffers from a severe headache after taking study medication
• a patient suffers from mild stomach ache for several days and cannot take
study medication
• a patient dies due to an illness unrelated to the trial
• a patient suffers a serious eye injury playing squash, leading to blindness.

36
Study conduct and GCP compliance
Serious adverse events
Some adverse events are classified as
serious adverse events (SAEs). These
have to be reported by the investigator
immediately to the sponsor – usually
by phone, e-mail or fax. The protocol
describes the procedures to be
followed. The sponsor should
have a 24-hour service to
deal with SAE reports.
The ICH GCP guidelines and
the ICH E2A guideline define
a serious adverse event or
reaction as any untoward medical
occurrence that at any dose
• results in death
• is life-threatening
• requires in-patient hospitalization
or prolongation of existing
hospitalization
• results in persistent or significant
disability/incapacity, or
• is a congenital anomaly/birth defect.
37
The term “life-threatening” in the
definition of serious adverse event
refers to an event in which the patient
was at risk of death at the time of
the event; it does not refer to an
event which hypothetically might
have caused death if it were
more severe.
ICH guideline E2A also
states that, “Medical and
scientific judgement should
be exercised in deciding
whether expedited reporting
is appropriate in other situations,
such as important medical events
that may not be immediately life-
threatening or result in death or
hospitalisation but may jeopardise the
patient or may require intervention
to prevent one of the other outcomes
listed in the definition above. These
should also usually be considered
serious”. These are sometimes
classified as “other significant
medical events”.
It should be noted that the severity of
an adverse event is not the same as
its seriousness. An event can be severe
but not serious, as it may not fall into
one of the above categories.

Adverse reactions
When an adverse event is considered
to have some causal relationship –
possibly, probably or definitely – with
the medicinal product, it is then called
an adverse reaction. Adverse reactions
(ARs) are called adverse drug reactions
(ADRs) in some countries.
The definition of an adverse reaction
in the ICH E2A guidelines, relating to
pre-marketed products, is as follows:
“all noxious and unintended responses
to a medicinal product related to any
dose should be considered adverse
drug reactions”.
The phrase “responses to a medicinal
product” means that a causal
relationship between a medicinal
product and an adverse event
is at least a reasonable
possibility, ie. the relationship
cannot be ruled out.
For marketed medicinal
products, a well-accepted
definition of an adverse drug
reaction in the post-marketing setting
is: “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 disease or for modification of
physiological function”.
38
Essential Good Clinical Practice
Expedited reporting of serious
adverse reactions
The regulatory authorities are
particularly interested in reports of
serious adverse reactions caused by
IMPs. The sponsor has to follow strict
rules in reporting these. When an
investigator reports a serious adverse
event to the sponsor, the following
procedure is followed.
• The sponsor will check that the
reported event is serious according
to the definition.
• The causality of the event (ie.
whether it is an adverse reaction)
will be determined, based on the
investigator’s assessment and
a further assessment by the
sponsor’s pharmacovigilance
experts. The investigator’s
opinion will not be
downgraded; however,
an adverse event might
be upgraded by the sponsor
to an adverse reaction,
based on previous experiences
with the product.
Study conduct and GCP compliance

• If it is an adverse reaction, the This should be followed by as

sponsor will then assess whether complete a report as possible within
or not the adverse event was 8 additional calendar days. This
expected or unexpected. An report must include an assessment
unexpected reaction is one in which of the importance and implication
the severity or frequency of the of the findings, including relevant
adverse reaction is not consistent previous experience with the same
with the current product or similar medicinal products.
information (eg. as described in
• Serious unexpected
the Investigator’s Brochure).
adverse reactions that
Adverse reactions that are are not fatal or life-
serious and unexpected – threatening must be
in Europe these are called reported as soon as
suspected unexpected serious possible, but no later than
adverse reactions (SUSARs) – must 15 calendar days after first
be expeditiously reported to the knowledge by the sponsor.
appropriate regulatory authority
according to a certain timescale.
• Fatal or life-threatening unexpected
adverse reactions occurring in
clinical investigations qualify for very
rapid reporting. Regulatory agencies
should be notified (eg. by telephone,
fax or in writing) as soon as possible,
but no later than 7 calendar days
after first knowledge by the sponsor.

39

Managing other safety reports
Sponsors require an effective
pharmacovigilance system to
manage safety reports. In Europe,
the person in charge of the
pharmacovigilance system is
called a Pharmacovigilance
Qualified Person (QPPV).
There is also a requirement
to have a local safety contact
working in conjunction with
the QPPV.
In addition to expedited reporting,
sponsors have to make annual
safety reports that include a listing
of the serious adverse reactions
and individual case safety reports.
The QPPV will co-ordinate this activity.
40
Essential Good Clinical Practice
All adverse events are recorded in
the CRFs. All collected safety data
are evaluated carefully during and
after the trial. At the end of the trial,
all adverse events – serious or not,
related to treatment or not –
will be summarized, analysed
and reported in the final
study report.
It is important that everyone
in an organization who might
encounter product safety
information – from receptionist
to Chief Executive – recognizes it
and knows how to report it to their
safety contact. This is an important
requirement of the pharmacovigilance
system.
Study conduct and GCP compliance

Example of a pharmacovigilance decision-making process by the sponsor

A patient with hay fever is taking part in a clinical trial of a new antihistamine
(the IMP). At the Week 3 visit the investigator discovers an abnormality
on an electrocardiogram (ECG) undertaken as part of the trial. The patient
is referred to a cardiologist, who immediately hospitalizes the patient for
3 days. The IMP is stopped and the patient recovers fully (with no further or
permanent ECG abnormalities). The event is not listed in the Investigator’s
Brochure.
• Is the event serious? Yes, because the subject is hospitalized.
• Is it an adverse reaction? Yes, because causality cannot be ruled out
(clue: the subject recovered when the IMP was stopped).
• Is it unexpected? Yes, because it is not listed in the Investigator’s Brochure.
The adverse event can therefore be reclassified as a suspected unexpected
serious adverse reaction (SUSAR). The event has to be reported expeditiously.
• Is the SUSAR immediately life-threatening or fatal? No.
Therefore the SUSAR has to be reported within 15 calendar days.

41
 Essential Good Clinical Practice

Analysis and reporting of trial data

Data collected in CRFs are checked by
the sponsor and any discrepancies or
missing data are accounted for.
The data are then entered into a
validated database prior to analysis.
The database is usually constructed by
the sponsor. It has to be tested prior to
use to ensure that it is fit for purpose.
There are important guidelines that
have to be followed relating to the
validation of computerized
systems used in clinical trials.
These are discussed further
in Chapter 4.
Checks are performed on
the database before it is
‘locked’. At this point, no further
alterations may be made or more
data entered.
Analyses are then performed. These
should be in keeping with the statistical
analysis plan documented in the study
protocol. Analysis and interpretation
are usually undertaken by a study
biostatistician.
A final study report is written – this
may be a team effort involving the
biostatistician, medical experts, the
investigator and the medical writer
who is preparing the report.
The final report describes the methods
used, summarizes and tabulates
the results obtained, and
provides interpretations of
the findings. Listings of all
data collected in the trial
form part of the final report.
It is very important that no
unplanned data analyses are
undertaken whilst the study is in
progress. These may introduce a
bias and thus affect the scientific
integrity of the study. Even tabulating
data to look for trends constitutes

REMEMBER:
In a blinded study, the study code is broken when the final
report is written. The investigator should not break any
study blinding unless in an emergency.
42
Study conduct and GCP compliance

an unplanned interim analysis. If an study team – will be used to examine

interim analysis of the data is data as the trial progresses,
planned before the study starts, to determine whether a
this will be taken into account determined outcome has
when estimating the sample been achieved. ICH guideline
size and it will be documented E9 (Statistical Principles
in the statistical analysis for Clinical Trials) is a useful
plan. Often, a Data Monitoring source of further information
Committee (DMC) – consisting of on this subject.
a group of experts independent of the

End of study procedures

The regulatory authority that The sponsor’s documents are collected
authorized the study and the relevant together in the Trial Master File (TMF),
ethics committee(s) should be informed which should be located in a safe and
when the trial has ended. In some secure environment. Access to the
regions (eg. Europe) this has to be done TMF should be restricted to authorized
within specified timescales at the end personnel. It is vital that the TMF is
of a trial (often defined as last subject, well defined as documents will be
last visit). located in many different places.
Documentation is the key to proving
that a study is in compliance with
GCP. Meticulous record keeping is
therefore vital. Essential documents –
see Chapter 4 – should not be stored
where they can be lost or damaged,
and files should always be kept
up-to-date.

43
 Essential Good Clinical Practice

Clear indexing and signposting is It is important that trial documents

required so that it is possible to locate are archived in a safe place at the end
trial documents quickly and efficiently of the trial. An index of the documents
when required. All documents held in an archive is essential.
have to be readily available
Although there are guidelines
on request by auditors and
on the length of time for
inspectors.
which trial documents need
After a trial has ended, the to be kept (eg. ICH GCP
sponsor is responsible for guidelines, Sections 5.5.7 –
archiving the TMF. 5.5.12), these vary from region
to region. In practice, a sponsor is
Whilst many documents are
unlikely to destroy trial documentation.
common to both the sponsor and
Sponsors will advise investigators
investigator sites, some are unique to
on the length of time to keep study
the study site (eg. the enrolment log,
documentation. Investigators should
signed consent forms and medical
expect this to be for a considerable
records such as patient files). It is
period, maybe 15 years or longer.
vital to preserve the integrity of these
documents. As storage space at the
investigator site is usually limited, the
sponsor may help the investigator
to ensure that these documents
are safely archived once the study
has ended.

REMEMBER:
A log of all TMF documents should be kept. Know where
each document is located. Clear signposting is required
so that all documents can be readily retrieved and made
available when needed.
44
Study conduct and GCP compliance
GCP compliance and inspections
Audits may be undertaken by sponsors.
This is to ensure that the sponsor’s
procedures are being correctly followed
and that the investigator site is
compliant with national laws, GCP
and the protocol.
Regulatory authority
inspections are undertaken to
check compliance.
Inspections are frequently
carried out by the authorities
in both their own countries and
in other territories. Inspections are
regularly undertaken by the US Food
and Drug Administration, the national
competent authorities in Europe which
also undertake inspections on behalf
of the European Medicines Agency,
and Japan’s regulatory body (the
Japanese Ministry of Health, Labour
and Welfare).
45
Inspections are often conducted on
a routine cyclical basis. The selection
of sponsors/ investigators for an
inspection may be based on risk
assessment (eg. those performing
more trials involving a greater
number of subjects are at
greater risk of inspection).
Unannounced inspections
may also be triggered by
complaints or adverse
publicity.
There may be severe penalties for
non-compliance with the regulations.
For example, inventing trial data will
certainly lead to criminal prosecution
and possibly a jail sentence. Non-
compliance with GCP will risk the study
data being rejected, as its reliability
cannot be ascertained. Investigators
in the USA can be banned from taking
part in clinical trials. Entire research
programmes in academic institutions
can be (and have been) closed down
temporarily or permanently.
 Essential Good Clinical Practice

Due diligence is the key

Due diligence is required when GCP should not be considered a burden.
performing clinical trials. A good rule to Remember, it is in place to protect the
remember is to document every aspect subjects who enter clinical trials and to
of the trial. If it is not written down make sure that the data collected are
and filed away, it didn’t exist! Mistakes useful and reliable.
are allowed, but these must be
documented and procedures should be
put in place to prevent their recurrence.
Everyone involved in a clinical trial has
a duty to be aware of their SOPs and
GCP responsibilities. Compliance will
usually be achieved if the protocol and
the organization’s SOPs are adhered to.

46
CHAPTER 4 Essential GCP

Essential study
documentation
Many of the documents that should • A log of all documents collected,
be part of the Trial Master File have and where they are stored, should
already been discussed. However, be kept.
numerous other documents that are
• Original documents are precious.
not listed in Section 8 of the ICH GCP
Once collected, they should not be
guidelines will also be generated and
removed from the files. Copies can
will form part of the overall study file.
be taken and these can be used as
There are some basic rules for working documents.
managing trial documents.
• Someone must be in charge of the
• A proper system of filing and storage trial files. The nominated person
is required, which might include the should ensure that there is no
use of filing cabinets. If this is the unauthorized access to documents.
case, specific drawers should be All trial files should be kept under
dedicated to the study. Avoid mixing lock and key.
up documentation in the same
filing area.
• Trial documents should not
be left around offices, waiting
rooms, clinics or other working
areas. Vital documents can get
lost and damaged, as well as
read by those who should not
be looking at them!

47
 Essential Good Clinical Practice

• The location of the filing area is are kept away from the office, even
important. The documents must be in a different country. Validated
stored securely in an adequate and copies will be acceptable in these
suitable space, free from risk of loss, circumstances.
premature destruction and damage.
• If documents are scanned
For example, thought must be given
or filmed, the copy must be
to how to protect the documents
validated to ensure that it is a true
from fire, floods, pests and other
reproduction of the original. This is
problems of nature. Inspectors
called a ‘certified copy’ and has all
will check that the file location
of the same content, context and
is suitable.
structure as the original document.
• When inspections occur, it is Documents should remain complete
important that the requested and legible throughout the required
documents can be retrieved retention period (ie. they are
efficiently. Sometimes documents enduring).

Computerized systems
The increasing use of computers in Guidelines on the use of computerized
clinical trials means that many of systems in clinical trials have been
the essential documents are in an published by the European Medicines
electronic format. For example, Agency1 and the US Food
data may be entered directly and Drug Administration2.
onto a computer by the Compliance with the current
investigator. The data are requirements helps to ensure
then transferred electronically that any data collected using
to the sponsor’s computerized computerized systems are
system. Laboratory data may validated3.
be sent directly to the sponsor’s
system.

1.
Inspectors in Europe check the compliance of a computerized system against the PIC/S guidance (Good Practices
for Computerised Systems in Regulated GxP Environments (PIC PI 011-3, September 2007)).
2.
The FDA has published guidance entitled ‘Computerized Systems Used in Clinical Investigations’, dated May 2007.
3.
 ll guidance is regularly updated to reflect current thinking, and requirements (such as those referred to above)
A
are changed.

48
Essential study documentation

There is an extensive list of • the system should be able to create

requirements for a computerized a complete record of all entries and
system, including the following: amendments (an ‘audit trail’)
• computerized systems used in trials • for quality auditing purposes, it
should be identified and listed should be possible to obtain clear
printed copies of electronically
• standard operating procedures
stored data
should be in place to cover system
set up, installation and use • stored data should be checked for
accessibility, durability and accuracy
• all critical systems should be
validated and tested. This should • data should be backed-up at regular
be based on a risk assessment with intervals
the key focus on human subject
• back-up data should be stored for as
protection and the reliability of the
long as necessary at a separate and
trial results
secure location.
• clear user manuals and suitable
training should be provided
• equipment should be located in
suitable places, where extraneous
factors cannot interfere with
the system
• data should only be entered or
amended by persons authorized
to do so
• there should be suitable methods for
deterring the unauthorized entry of
data, including the use of keys, pass
cards, personal codes and restricted
access to computer terminals

49
 Essential Good Clinical Practice

Checklists of trial documents

Some of the many documents that
make up the Trial Master File, as well
as other essential documents, are
listed below. These lists demonstrate
the vast quantity of documentation
that can make up a typical clinical trial.
The lists below from Section 8 of
ICH GCP are intended as guidance
only. There is no standard document
checklist – every trial is different and
will generate its own documents.
Furthermore, as new regulations are
implemented, new documentation will
be generated, and new standard forms
are being developed all the time.

Pre-study documents
Sponsor Investigator
4 4 Investigator’s Brochure
4 4 Signed protocol and amendments
4 4 Subject information sheet and consent form
4 4 Written instructions for subject
4 4 Advertisement for recruitment
4 4 Financial agreement with investigator
4 Contract research organization (CRO) agreement (if any)
4 4 Insurance statement
4 4 Investigator agreement
4 4 Independent ethics committee (IEC)/institutional review
board (IRB) opinion on final protocol, information sheets,
consent form, recruitment advertisements, etc
4 4 IEC/IRB composition
4 4 Agreement with pharmacy
4 4 Regulatory opinion notification
4 4 CVs of relevant study site staff
4 4 CV of principal investigator
4 4 Reference ranges for laboratory evaluations
4 4 Reference ranges for study tests
4 4 Laboratory procedures and quality assurance (QA)
records

50
Essential study documentation

Sponsor Investigator
4 4 Laboratory certification/accreditation
4 Sample of label (investigational medicinal product; IMP)
4 4 Handling instructions (IMP)
4 4 Shipping records (IMP)
4 (4) Certificate of analysis (IMP)
4 4 Signing off IMP by Qualified Person (QP)
4 4 Decoding procedures
4 Master randomization list (blinded)
4 Pre-trial monitoring report (of site)
4 4 Study initiation report
4 4 Investigator’s study personnel log
4 4 Manufacturing/import authorization for IMPs (if
required)
4 4 Documentation relating to any Data Monitoring
Committee
4 4 Final case report form (CRF)
4 4 Documents relevant to investigational new drug (IND)
applications (eg. Form FDA 1572), if any
4 Statistical analysis plan
4 Blank CRF

During study documents

Sponsor Investigator
4 4 Investigator’s Brochure updates
4 4 Amendments to protocol, subject information sheet,
consent form, CRF updates, advertisements
4 4 IEC/IRB opinion for updated documents
4 4 Documents relating to applications for amendment to
protocol
4 4 Regulatory opinion of amendments
4 4 IEC/IRB notification of continuing review
4 4 CVs of new staff continued

51
 Essential Good Clinical Practice

During study documents continued

Sponsor Investigator
4 4 Updates to reference ranges
4 4 Updates to laboratory procedures
4 4 Records of product shipment to investigator
4 (4) Certificates of analysis for new IMPs
4 4 Signing off new IMP by QP
4 Monitoring visit reports
4 4 Log of monitoring visits made to site
4 4 Letters and other records of communication with study
site
4 4 Completed CRF pages (sponsor – original; investigator
– copy)
4 4 Documented changes to CRFs
4 4 Signature sheet (those making CRF entries/corrections)
4 4 Notifications of serious adverse events (investigator to
sponsor)
4 (4) Notifications of serious adverse reactions (sponsor to
authorities)
4 4 Safety information provided to investigators
4 4 Safety updates to competent authorities
4 4 Safety information provided to IEC/IRB
4 4 Annual report to IEC/IRB
4 4 Product accountability at study site
4 4 Record of retained samples and body fluids/tissues
4 4 Updates to investigator’s study personnel log
4 4 Documentation and explanation by investigator of any
protocol deviation
4 4 Communication from monitor/sponsor to investigator on
protocol deviations
4 Code-break envelopes

52
Essential study documentation

Post-study documents

Sponsor Investigator
4 4 Final product accountability at study site
4 4 Documentation relating to product destruction
4 Audit certificate(s)
4 Final study close-out report
4 Treatment allocation and master decoding information
4 4 Final clinical study report
4 4 Notification to authorities of end of trial
4 4 Notifications to IEC/IRB about study end
4 4 List of archived documents and location (archive index/
log)
4 4 List of Standard Operating Procedures and versions used
during trial
4 4 Completed list of sponsor/CRO personnel involved in
study
4 4 Details of any transfer of ownership of study-related
documentation
4 4 Identification of archivist(s)
4 4 Written information to investigator regarding record
retention

Investigator site only

Sponsor Investigator
4 Signed consent forms
4 Source documents, eg. patient files
4 Subject identification list
4 Subject screening log
4 Subject enrolment log
4 Copies of completed CRF pages
4 Documented changes to CRFs (copy)
4 Subject consent to allow viewing by third parties
of patient files continued

53
 Essential Good Clinical Practice

Investigator site only continued

Sponsor Investigator
4 Authority of subject to contact primary care physician
4 Final report by investigator to IEC/IRB/regulatory
authority (where required/applicable)
4 Consent of subject to process and transfer personal data

Sponsor general files

Sponsor Investigator
4 List of SOPs and versions used
4 Internal meeting minutes
4 CVs of sponsor trial staff
4 Training records of sponsor trial staff
4 Study audit reports (in QA files not general Trial Master
File)
4 Correspondence with regulatory authorities
4 Meetings with regulatory authorities
4 Scientific advice
4 Documentation relating to inspections
4 Out-of-date/draft versions of trial documentation
(eg. protocol)
4 Master randomization list (unblinded)
4 Trial registration documentation, eg. EudraCT, Clinical
Trial Authorization/IND application
4 Manufacturing and/or import authorization
4 Sponsor’s quality control records

The location of some documents may vary (eg. a certificate of IMP analysis might
not always be copied to the investigator’s file). A sponsor’s SOPs will determine
which documents are kept in sponsor files only. Original CRF pages will be kept at
the study site until collection by the sponsor. Thereafter, the investigator will retain
a copy of the CRF pages.

54
CHAPTER 5
The sponsors’ quality
management system
A major change to the ICH GCP
guidelines in 2016, brought about
by the E6(R2) addendum, was the
introduction of guidance on quality
management.
Sponsors should implement
a system to manage quality
throughout all stages of the trial
process. The system should focus
activities on the protection of trial
subjects and the reliability of data.
This includes the design of efficient
protocols, CRFs and other trial
documents, and trial processes
should avoid unnecessary complexity.
A risk-based approach should
55
Essential GCP
• identify critical processes to
ensure subject protection and
data reliability
• identify risks at both the system
and trial level
• evaluate the identified risks
• decide which risks to control, accept
or reduce and establish predefined
tolerance limits
• communicate quality management
activities to those who are affected
by such activities
• periodically review risk control
measures
• describe the quality management
approach and summarize important
deviations from the predefined
tolerance limits, plus any remedial
actions, in the clinical study report.
 Essential Good Clinical Practice

A documented risk assessment is a When considering the risks in a trial,

fundamental requirement for all trials. many factors have to be considered,
It should identify both the higher including
risk and lower risk areas of
• the personnel
the trial. For the higher risk
areas, thought must be • the vendors
given to how risks can be • the medicinal product
mitigated. These actions
should be documented and • blinding
their effectiveness assessed • safety and adverse events
once the trial is in progress. For lower
• data collection
risk areas, the risks may be deemed
acceptable without the need for • the investigators and sites
further action.
• the consent process
• the size and complexity of the trial
and assessments.

REMEMBER:
Risk assessments are now a vital part of every clinical trial.
These should focus on human subject protection and data
reliability. Risks should be constantly monitored by both the
investigator and sponsor as the trial progresses.
56
The sponsors’ quality management system
Risk-based approach to trial monitoring
A trial must be monitored. Those
undertaking trial monitoring must be
competent and qualified by experience
and training; a good monitor will have
a wide range of skills. The purpose of
monitoring is to verify that the rights
and well-being of the subjects who
participate in a trial are protected.
Furthermore, monitoring confirms
that an enrolled subject exists.
Monitoring also checks the integrity
of trial data and ensures that the data
are accurate, complete and verifiable
from source documents.
Finally, monitoring checks are made
to determine if the trial has been
conducted in accordance with the
regulatory requirements, the
study protocol and trial plan
and, of course, GCP. Effective
monitoring can detect
problems early and prevent
issues with human subject
protection and the integrity of
the data being collected.
Co-monitoring is often undertaken
as part of the quality management
process relating to trial monitoring
oversight. Co-monitoring ensures
that monitors are performing their
duties correctly and in accordance
with the organization’s SOPs and
monitoring plan.
57
According to ICH GCP, sponsors should
develop a systematic, prioritized,
risk-based approach to the monitoring
of clinical trials. This is a flexible
and varied approach to monitoring
to improve its effectiveness and
efficiency. The major regulators
in Europe and the USA encourage
this modern approach, although
regulators in other regions have not
been so accepting of it. Sponsors
have therefore been cautious when
adopting risk-based approaches to
trial management.
Risk-based monitoring may involve
more targeted monitoring visits to
the investigator site. Greater
emphasis may be placed by
sponsors (or contract research
organizations acting on
behalf of a sponsor) on
remote monitoring, such
as via telephone calls and
monitoring data centrally using
validated computerized systems.
The sponsor may choose on-site
monitoring, a combination of on-site
and centralized monitoring, or –
when it can be justified – centralized
monitoring only.

Data management has a big role
to play in risk-based approaches to
trial monitoring (RBM) and quality
management. Together with the
biostatistician, the data manager
should therefore have input into the
monitoring plan and the selection of
appropriate data monitoring tools.
They should also have input into the
risk assessment, particularly
in relation to data integrity
issues. The identification
of critical data and plans
to protect data integrity
are crucial. Data managers
should also have appropriate
data integrity input into risk
identification, risk evaluation, risk
control, communication, review and
reporting. Data managers may also
have a significant impact on blinding
methods and the impact of breaches.
58
Essential Good Clinical Practice
Centralized monitoring
Centralized monitoring involves
the review of accumulating data
and can be used to identify missing
and inconsistent data and protocol
deviations, and in trend and metrics
analyses. It has to be performed
in a timely manner by suitably
qualified and trained persons. Medical
reviewers, trial managers, data
managers and biostatisticians
have a significant part to play
in this.
This method of remote
monitoring can be used to
identify the need for site visits
and maximize the effectiveness of
site management.
The FDA guidance supports risk-based
approaches to monitoring clinical trials.
It argues that the types of monitoring
activities and the extent to which
centralized monitoring practices can be
employed depend on various factors.
The sponsors’ quality management system

These include the sponsor’s use of • examine data trends such as the
electronic systems, the sponsor’s range, consistency and variability of
access to subjects’ electronic records, data within and across sites
the timeliness of data entry
• check for systematic or
from paper CRFs, and the
significant errors in data
communication tools
collection and reporting at
available to the sponsor
a site or across sites, or
and study site. Sponsors
potential data manipulation
who plan to use centralized
or data integrity problems
monitoring processes should
ensure that the processes and • analyse site characteristics
expectations for site record keeping, and performance metrics
data entry and reporting are well- • select sites and/or processes for
defined and ensure timely access targeted on-site monitoring.
to clinical trial data and supporting
documentation.
According to ICH GCP E6(R2) Section
5.18.3, centralized monitoring
processes can be used to:
• identify missing data, inconsistent
data, data outliers, unexpected lack
of variability and protocol deviations

Three key monitoring activities:

On site Remote Centralized
• Visit to site • Telephone calls • Data review
• Meetings with • Internet meetings • Statistical review
study team
• E-mail, etc • Variability, trend
• Data verification analysis

59
 Essential Good Clinical Practice

Some of the metrics that might be When centralized monitoring is

measured include serious adverse undertaken the activities must be
event reporting, time to CRF documented formally. The reporting
completion, numbers of deviations of activities should be regular
from predefined tolerance limits, – these reports form an
rates of withdrawals and important part of the Trial
rates of eligibility criteria Master File and subsequent
breaches. document archive. The
reports should be detailed
Central monitoring activities
enough to demonstrate
should be undertaken early
that the activities defined in
and well before the end of a
the monitoring plan have been
trial. Anything detected that falls
undertaken. Any deviations from the
outside the predetermined tolerance
plan must be explained and justified.
limits should then be used to trigger a
monitoring visit and perhaps prevent
further protocol violations or data
integrity issues.

REMEMBER:
As risk-based monitoring may involve fewer visits by the
sponsor’s monitor to the investigator site, the investigator
must take on greater responsibility for ensuring that the
study is conducted correctly and must ensure proper
oversight of the trial at all times.
60
The sponsors’ quality management system
Monitoring plan
Whichever methods the sponsor uses
to monitor the trial, the strategy,
methods, responsibilities and
requirements for trial monitoring
must be documented in a monitoring
plan. This plan must be adhered to
– compliance with it will be checked
during a regulatory inspection. In some
regions (eg. the USA) the monitoring
plan can be submitted to the regulator
for an opinion on its acceptability.
Review of monitoring activities
Reports of both on-site and centralized
monitoring should be maintained by
the sponsor. These should be reviewed
and followed up on a timely basis to
ensure that activities are in compliance
with the monitoring plan. A periodic
review of the monitoring plan is
required so that any emerging issues
can be considered and adaptations can
be incorporated, as appropriate.
61
Dealing with identified non-
compliance
If non-compliance with the protocol,
SOPs, GCP or the regulatory
requirements is detected that does
or may affect subject protection
or the reliability of the trial results,
the sponsor should perform a root
cause analysis and implement – and
document – appropriate corrective and
preventative actions.
These activities must be documented
and will form part of the sponsor’s
Trial Master File. All deviations should
be evaluated and the decision to
consider them as significant or non-
significant should be a transparent,
documented process.
QUIZ Essential Good Clinical Practice

Test your knowledge

1. What is good clinical practice? 4. Which accepted code of practice
describes the investigator’s
A) A quality standard applied
ethical principles applicable in
to trials in order to improve
global clinical trials?
subject protection and the
quality of data collected in A) Declaration of Helsinki
the trial
B) Code of Federal Regulations
B) Best practices in medicine
C) European Directive
and surgery
2003/94/EC
C) An international standard
devised by pharmaceutical 5. What are Standard Operating
companies to ensure that their Procedures (SOPs)?
trials are performed correctly
A) Documented procedures
and systems that describe
2. Who is affected by GCP?
all trial processes to ensure
A) Sponsors, investigators, ethics compliance with regulations
committees and the organization’s policies
B) Only the study sponsor B) The procedures to be followed
by trial monitors when
C) Only the study investigator
assessing the suitability of an
and ethics committee
investigational site
3. What is meant by the term ICH? C) Guidelines to be followed
by a study nurse at the
A) International Clinical Hospital
investigational site
group
B) International Clinical
Harmonisation of trials
C) International Council for
Harmonisation

62
Quiz
6. What impact does GCP
implementation have on clinical
trials? Choose 3 answers.
A) Facilitates better subject
protection
B) Facilitates collection of
credible data
C) Facilitates better study
documentation
D) Requires annual inspections
and audits
E) Facilitates better standards in
non-clinical studies
7. True or false?
Available non-clinical and clinical
information should be adequate
to support the proposed clinical
trial.
8. True or false?
The rights, safety and well-being
of the trial subjects are the most
important considerations but
need not prevail over interests
of science and society.
63
9. True or false?
All clinical trial information
should be recorded, handled and
stored in a way that allows its
accurate reporting, interpretation
and verification irrespective of
the media used.
10. In addition to following
GCP guidelines, what other
requirements should a study
sponsor always adhere to?
Choose 2 options.
A) N
 ational legislation of the
country where the trial is being
carried out
B) Sponsor’s own Standard
Operating Procedures (SOPs)
C) Only EU Directives and
Regulations relating to
clinical trials
D) Only FDA guidance documents
Answers on page 70.

11. According to GCP, how should
the investigator show that
he/she has the appropriate
qualifications and experience
to do the study?
A) Providing an up-to-date,
signed and dated CV
B) Providing a copy of the
certificate of medical
registration
C) Providing the CV used to obtain
the current position
12. True or false?
Trial sponsors are required to
have insurance to cover the
compensation of trial subjects
in the event of product-related
damage and also to indemnify
investigators.
13. How should a researcher become
familiar with the investigational
product to be used in a clinical
trial?
A) U
 ndertaking a self-designed
pilot study in a few patients
prior to the study
B) O
 btaining and reading the up-
to-date Investigator’s Brochure
from the sponsor of the trial
C) R
 eading literature relevant to
that therapeutic area
64
Essential Good Clinical Practice
14. How does GCP require the
informed consent of a trial
subject to be obtained?
A) Obtain written informed
consent from each subject
before they undertake any
study-related procedures
B) Obtain verbal consent as long
as this is undertaken before the
study starts
C) O
 btain consent once it has
been determined that the
subject is suitable for the study
after undertaking baseline
assessments
15. Which of the following are
required to ensure consent is
correctly documented?
Select 2 answers.
A) Consent form is signed and
dated by the person obtaining
consent
B) Consent form is signed by
the subject but dated by the
investigator
C) Consent form is signed and
dated by the subject
D) A witness is always required to
sign the consent form
Quiz

16. True or false? 18. According to ICH GCP, which

A log identifying subjects items require the ‘favourable
recruited to the study should opinion’ (‘approval’) of an ethics
be kept by the investigator and committee? Select 3 answers.
a photocopy of this should be
A) Protocol and any subsequent
handed to the sponsor/monitor
amendments
at the end of the trial?
B) Consent form and subject
17. A patient is considered by the information sheet
investigator to be suitable for C) Investigator’s Brochure
entry into the study. However
the patient is 6 months too old, D) Case report form
according to the exclusion criteria E) Recruitment methods
in the protocol. What should the (eg. advertisements, posters)
investigator do in order to fully
comply with GCP and regulatory
19. Select 3 options that apply
requirements?
to the use of equipment in
A) T he investigator may obtain a clinical trial.
permission from the sponsor to
A) It should be calibrated and
enter the patient
the results documented
B) T he investigator should not
B) It should be purchased
enter the patient as it would be
specifically for the trial
a protocol violation
C) The equipment should
C) T he investigator can amend the
be regularly maintained
protocol and then inform the
and documented in a
sponsor
maintenance log
D) The equipment should be
available for use when it is
required for trial purposes
E) N
 ormal health service
equipment may be used
without calibration or
maintenance

65 Answers on page 70.


20.  Whilst collecting samples as part
of a clinical trial, a subject faints.
The investigator is about to take
the timed 1-hour blood sample
from the subject. The event
means that the sample will now
be taken 20 minutes late. What
should happen?
A) T ake the sample and label it as
a 1-hour sample, making no
file notes
B) T ake the sample and make a
file note that it was collected
late, giving the reason why
C) M
 iss the sample completely
and take the next scheduled
sample, making no file notes
21. Which essential documents are
only kept by the study site with
no copy retained by the sponsor?
Select 3 answers.
A) Signed consent forms
B) Subject identification log
C) F inal signed version of protocol
D) Patient or subject files
E) Product accountability records
66
Essential Good Clinical Practice
22. True or false?
The filing cabinet containing the
essential documents for the trial
should be left unlocked, and in an
area that allows general access.
23. True or false?
The names of subjects should not
be recorded in case report forms
to preserve confidentiality.
24. When completing case report
forms, investigators should
ensure that .... Select 3 answers.
A) There are no missing data
B) Data are recorded accurately
C) Data are legible
D) Incorrect data are hidden using
correcting fluids
E) A
 ll data are entered at the end
of the study
25. What best describes the term
“source document”?
A) The place where data are
recorded in the first practicably
retainable place
B) Always the case report form
C) Always the patient file
Quiz

26. How should data be changed in a 28. Which of the following would be
case report form? classified as a serious adverse
event?
A) C
 ross out the original entry
with a single line, enter the A) Severe headache experienced
new data alongside, date and in the no treatment run-in to
initial the change the study, painkillers prescribed
B) E
 nsure that the original data B) Dizziness thought by the
are completely covered, enter investigator to be possibly
the new data alongside, date related to study medication;
and initial the change subject managed at home
C) W
 ait for the sponsor’s monitor C) S ickness in a patient taking
to review the case report forms placebo, hospitalized for 2 days
and then ask the monitor to for rehydration therapy
make the necessary change
D) Chest pain considered by the
investigator to be related to
27. What best describes an adverse trial medication, treated in an
event? emergency room but released
A) A
 n unwanted medical from hospital after 2 hours
occurrence in a trial subject
that may or may not be caused
by the study medication
B) A
 n unwanted medical
occurrence in a trial subject
that is caused by the study
medication
C) A
 ny event that leads to the
subject being hospitalized,
probably caused by the
study medication

67 Answers on page 70.

 Essential Good Clinical Practice

29. Which of the following 31. What is product accountability?

relationships to trial medication
A) The process of accounting
would mean that an adverse
for every dose of medication
event is upgraded to an adverse
in a clinical trial from its
reaction? More than one answer!
manufacture to destruction
A) Definitely related to treatment
B) Tracking the amount of
B) Causal relationship cannot be
investigational product
ruled out
delivered to the investigator
C) Considered unrelated to site
treatment by both the
investigator and sponsor C) Records
 that indicate that
the investigational product
D) Considered unrelated to
has been manufactured
treatment by the sponsor but
in accordance with Good
possibly related to treatment
Manufacturing Practice
by the investigator
32. True or false?
30. Which of the following would be
Investigational medicinal product
classified as adverse reactions?
can still be used to treat the
Select 2 answers.
investigator’s patients who do
A) S evere headache experienced not fulfil trial entry criteria as
in the no treatment run-in to long as a case report form is
the study, painkillers prescribed completed.
B) D izziness thought by the
investigator to be possibly
related to study medication;
subject managed at home
C) S ickness in a patient taking
placebo, hospitalized for 2 days
for rehydration therapy
D) Chest pain considered by the
investigator to be related to
trial medication, treated in an
emergency room but released
from hospital after 2 hours
68
Study conduct and GCP compliance
Quiz
33. Where should all specific trial-
related documentation be kept?
A) F or the required period of time
in a Trial Master File that is
secure with limited access
B) F or the required period of
time in a Trial Master File
with unrestricted access to
investigators and monitors
C) In a secure third-party storage
facility with access controlled
by the investigator
69
34. What are the potential
consequences of failing to
adhere to good clinical practice
guidelines when performing a
clinical trial on an investigational
product? Select 2 answers.
A) The trial results could be
rejected and those involved in
the trial may face sanctions
B) Nothing at all; GCP is optional
with no legal requirement to
comply
C) T his may trigger an inspection
by the regulatory authorities
D) In all cases the investigator
and sponsor will face criminal
prosecution with no chance
of remedy
Answers on page 70.
ANSWERS Essential Good Clinical Practice

Answers to quiz
1. A 13. B 25. A
2. A 14.  A 26.  A
3. C 15. A, C 27.  A
4.  A 16. False 28. C
5. A 17.  B 29. A, B, D
6.  , B, C
A 18. A, B, E 30. B, D
7. True 19. A, C, D 31.  A
8. False 20.  B 32. False
9. True 21. A, B, D 33.  A
10. A, B 22. False 34. A, C
11. A 23. True
12. True 24. A, B, C

70
Good Clinical Practice (GCP) is a global quality process that is applied to the
conduct of all clinical trials on new medicinal products. This book aims to
explain the key areas of GCP to help both the non-technical and technical
undertake their roles more effectively. It is based on the internationally
accepted GCP guidelines of the International Council for Harmonisation
(ICH) and encompasses the changes made in 2016 in version E6(R2).

Professor David Hutchinson is an internationally renowned teacher and writer

specializing in clinical research and GCP. He spent many years as an organizer
and manager of clinical trials on new drugs before, during and after the ‘birth’ of
GCP. His books include the best-selling 12 Golden GCP Rules for Investigators,
as well as 15 Golden IND/GCP Rules for Investigators and10 Golden Rules for
Pharmacists. He has taught GCP to personnel from more than 50 countries
worldwide, including investigators, research nurses, physicians and research
associates in the pharmaceutical industry, university students, regulatory
authorities and members of national ethics committees. He is currently Editor
and Publisher of Clinical Research and Quality Assurance Advisor.

www.canarybooks.com