Essential GCP by Professor David Hutchinson

Essential
CP
Good Clinical
Practice
© Professor David Hutchinson
Acknowledgments
The author would like to thank Tony Moore, Neil Mountain and Vanessa Fellows for the
production of cartoons and illustrations used in this book.
Published by Canary Ltd, PO Box 9, Guildford, Surrey GU3 2WZ, UK

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First edition, January 2009
ISBN 978-1-903712-66-5
EAN 9781903712665
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Design: Lisa Ivil, LIMA Graphics, Guildford, Surrey, UK
Print: Surrey Litho, Great Bookham, Surrey, UK
Essential
Good Clinical
Practice
CP
by Professor David Hutchinson
Essential Good Clinical Practice
Contents
Preface iii
Chapter 1: Introduction to good clinical practice 1
Factors affecting clinical trials 1
GCP development 3
Principles of GCP 7
Compliance with GCP 8
Documenting GCP compliance 9
Test your knowledge 10
Chapter 2: General GCP responsibilities and 13

subject protection
The investigator and study site 13
Addressing the risks of trials 15
Management of investigational medicinal product 17
The study protocol 19
Recruiting trial subjects 20
Subject protection 21
Chapter 3: Collecting and recording trial data, 29

including safety monitoring and reporting
Data collection in clinical trials 29
Safety monitoring, recording and reporting 33
Analysis and reporting of trial data 39
End of study procedures 40
GCP compliance and inspections 41
Due diligence is the key 41
Chapter 4: Essential study documentation 45

Computerised systems 46
Checklists of trial documents 47
Answers to tests 53
ii
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
Conference on Harmonisation (ICH E6 revision 1). The guidelines (ICH
GCP) have become a proven international standard that is globally
recognised 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 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 and documentation.
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
iii
Chapter 1: Introduction to good
clinical practice
Factors affecting clinical trials

Everyone involved in clinical trials in humans has a responsibility to
ensure that the trials are conducted to the highest possible standards.
Around 25 years ago there were few rules and regulations affecting
clinical trial conduct. Most sponsors and investigators were free to
design and undertake trials as they wished. A few voluntary codes
existed.
Today, human clinical research is heavily regulated. A quality standard
called good clinical practice (GCP) should be followed in all trials,
wherever they are conducted.
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 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 (Seoul, 2008) can
be obtained from the WMA website at <www.wma.net>.
1
Other regulations and guidelines

A process called ICH (International Conference on 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 try to harmonise procedures throughout Europe.
These have been incorporated into the national laws of EEA Member
States. Whilst there has not been complete harmonisation between
European countries, there are many similar procedures, making pan-
European trials easier to perform.
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.
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.
Europe accounts for about one-third of patients recruited

into clinical trials submitted as part of marketing authorisations.
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 recognised GCP.
2
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 summarise 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 results collected
are accurate and
reliable.
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 organise, manage and fund clinical trials, such
as pharmaceutical companies (and other commercial organisations) and
non-commercial organisations
• investigators – physicians or dentists and members of their study teams,
such as other doctors, nurses and administrators
• ethics committees.
3
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
authorisation 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.
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
harmonised 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.
Harmonisation of procedures
The EU prompted a meeting to discuss the wider harmonisation 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.
The conference has since developed into an effective and highly successful
process to provide guidance on all aspects of drug development, known
simply as ICH. The ICH website contains a great deal of useful information
about the process, including its products and plans for the future (see
<www.ich.org>).
All ICH topics are determined by a Steering Committee that appoints
experts in the field to develop guidelines. The Steering Committee is made
up of regulators from the EU, Japan and the USA, and delegates from the
associations representing the pharmaceutical companies in those regions:
• regulators: European Commission (EU); Japanese Ministry of Health,
Labour and Welfare (MHLW); and the US Food and Drug Administration
(FDA)
4
• pharmaceutical industry representatives: European Federation of

Pharmaceutical Industries’ Associations (EFPIA); Japan Pharmaceutical
Manufacturers Association (JPMA); and Pharmaceutical Research and
Manufacturers of America (PhRMA).
Observers also participate in Steering Committee meetings. The observers
comprise representatives from the World Health Organization (WHO), the
European Free Trade Association (EFTA) and Canada (represented by
Health Canada). This important group of non-voting members acts as a
link between the ICH and non-ICH countries and regions.
The ICH process has produced a great deal of useful guidance covering
all aspects of drug development. This includes guidance relating to the
quality of medicines (the ‘Q’ guidelines), guidance on non-clinical safety
studies (the ‘S’ guidelines), guidance on studies in humans (the ‘E’
guidelines) and guidance on miscellaneous topics (the ‘M’ guidelines).
The E guidelines are the most important products for human clinical trials.
A summary of the ICH products in the E section is provided below.
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: Definitions for genomic biomarkers, pharmacogenomics,
pharmacogenetics, genomic data and sample coding categories.
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.
5
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 and many other countries.
The ICH GCP guidelines are divided into eight sections. Sections 3 to 5
outline responsibilities for those involved in trials:
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.
The ICH GCP requirements broadly focus on three main areas: subject
protection, the quality 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 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.
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.
6
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).
• 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.
• 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.
7
• All clinical trial information should be recorded, handled, and stored in a

way that allows its accurate reporting, interpretation and verification.
• 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.
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.
Organisations are able to ensure that their staff comply with GCP
requirements by establishing a set of Standard Operating Procedures
(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.
8
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.
If it is not documented, it didn’t happen!
Documents are generated before, during and after a trial. They are called
essential documents. 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).
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.
The minimum content of the study file at both

the sponsor and investigator sites is listed in
Section 8 of the ICH GCP guidelines.
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.
9
Test your knowledge

1. What is Good Clinical C) Europe
Practice? D) Asia
A) A quality standard applied to E) Australasia
trials in order to improve
subject protection and the 5. Which accepted code of
quality of data collected in practice describes the
the trial investigator’s ethical
B) Best practices in medicine principles applicable in
and surgery global clinical trials?
C) An international standard A) Declaration of Helsinki
devised by pharmaceutical B) Code of Federal Regulations
companies to ensure that
C) European Directive
their trials are performed
2003/94/EC
correctly
6. What are Standard Operating
2. Who is affected by GCP?
Procedures (SOPs)?
A) Sponsors, investigators,
A) Documented procedures
ethics committees
and systems that describe all
B) Only the study sponsor trial processes to ensure
C) Only the study investigator compliance with regulations
and ethics committee and the organisation’s
policies
3. What is meant by the term
ICH? B) The procedures to be
followed by trial monitors
A) International Clinical Hospital when assessing the
group suitability of an
B) International Clinical investigational site
Harmonisation of trials C) Guidelines to be followed by
C) International Conference on a study nurse at the
Harmonisation investigational site
4. Which countries/regions 7. What impact does GCP
came together to develop the implementation have on
ICH process? Choose 3 clinical trials? Choose 3
answers. answers.
A) Japan A) Facilitates better subject
B) USA protection
10
B) Facilitates collection of recorded, handled, and

credible data stored in a way that allows
C) Facilitates better study its accurate reporting,
documentation interpretation and
D) Requires annual inspections verification.
and audits
11. In addition to following
E) Facilitates better standards GCP guidelines, what other
in non-clinical studies requirements should a study
sponsor always adhere to?
8. True or false? Available Choose 2 options.
non-clinical and clinical
information should be A) National legislation of the
adequate to support the country where the trial is
proposed clinical trial. being carried out
B) Sponsor’s own Standard
9. True or false? The rights, Operating Procedures
safety, and well-being of the (SOPs)
trial subjects are the most C) Only EU Directives relating
important considerations but to clinical trials
need not prevail over interests
of science and society. D) Only FDA guidance
documents
10. True or false? All clinical
trial information should be Answers on page 53.
11
Chapter 2: 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.
The investigator must have time to undertake the

study, sufficient potential trial subjects, and suitable facilities
and supporting staff.
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.
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.
13
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.
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.
Equipment requirements
The study site must have the relevant equipment and facilities in order to
perform the trial. Equipment used 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.
14
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.
The risks of each study should be carefully evaluated by the sponsor and
investigator, and plans put into place to both minimise risks to subjects and
deal with any unforeseen event.
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 Directives implemented into national laws make 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.
15
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.
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.
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.
16
Even if an adverse reaction causing the injury was foreseeable or

predictable – and regardless of the fact that the patient has freely
consented to take part in the trial – this should not exclude a patient
from consideration for compensation.
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.
The information in the Investigator's Brochure should be

presented in a concise, simple, objective, balanced and non-
promotional form.
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.
17
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.
IMPs should be stored securely in suitable conditions, with access by
authorised 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).
18
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).
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.
Finally, it is not acceptable for a sponsor of a trial to allow an investigator to
enter subjects who do not strictly fulfil the entry criteria, or to permit any
other deviation from the protocol using waivers. Waivers breach ethics and
regulatory approval, and may have serious implications for the statistical
integrity of the study.
19
Protocol amendments
It is possible to amend a protocol during a trial. However, there are strict
procedures for doing this and ad hoc changes must not be implemented
without the proper approvals. 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. In
Europe, procedures for the approval of ‘substantial amendments’ are
documented in national law. These involve notification of
both the competent (regulatory) authority and the ethics
committee. The sponsor will help investigators to comply
with this process.
In the event of an emergency involving an immediate
hazard, it is possible to amend the protocol to protect trial
subjects at risk. However, the correct process of informing
the sponsor and ethics committee must then be followed.
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.
20
Subject enrolment log

Information about subjects who have been screened and entered into
the trial should be recorded in a 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.
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 Europe, a standard application form is
used. The IEC/IRB will then review the application and provide its opinion. In
Europe, this opinion is to be given within 60 days, unless the product is a
biological or gene/cell therapy, when longer review periods are permitted
(90 days). In other regions there may be no timeline established and obtaining
an ethics committee opinion may be a significant rate-limiting step.
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.
21
Consent procedures
Freely given written informed consent is required before any subject enters
the trial and any trial-related assessments are undertaken (including those
that would usually be conducted as part of normal clinical practice: if the
data are recorded for the trial, they are considered trial-related!)
Each prospective subject must be provided with information verbally and
in writing using an approved subject information sheet. In some countries
(eg. the USA), the document may need to bear the stamp of the approving
ethics committee.
ICH GCP Section 4.8.10 requires the information sheet to contain 20 items
of information. The subject information sheet tends to be quite a long
document, but should be presented in a simple, plain-language format.
Subjects should be given ample time to decide about the trial. They must
not be coerced into participation. They are always free to withdraw from the
study at any time, even though they initially gave consent to participate. It
is good practice to check that the subject understands the information
before he/she signs the consent form.
When subjects cannot consent for themselves (eg. children), are unable to
read or write, or are mentally impaired, special consent procedures exist.
These are laid down in national law. In these cases a witness or a legal
representative may be required.
22
Information to be provided
The items of information to be presented to trial subjects are stated in
the 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.
(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.
23
(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.
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.
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.
24
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.
Test your knowledge

1. According to GCP, how A) Undertaking a self-designed
should the investigator show pilot study in a few patients
that he/she has the appro- prior to the study
priate qualifications and B) Obtaining and reading the up-
experience to do the study? to-date Investigator’s Brochure
A) Providing an up-to-date, from the sponsor of the trial
signed and dated CV C) Reading literature relevant to
B) Providing a copy of the that therapeutic area
certificate of medical
registration 4. How does GCP require the
informed consent of a trial
C) Providing the CV used to subject to be obtained?
obtain the current position
A) Obtain written informed
2. True or false? Trial sponsors consent from each subject
are required to have insurance before they undertake any
to cover the compensation of study-related procedures
trial subjects in the event of B) Obtain verbal consent as
product-related damage long as this is undertaken
and also to indemnify before the study starts
investigators.
C) Obtain consent once it has
3. How should a researcher been determined that the
become familiar with the subject is suitable for the
investigational product to be study after undertaking
used in a clinical trial? baseline assessments
25
5. Which of the following are C) The investigator can amend

required to ensure consent the protocol and then inform
is correctly documented? the sponsor
Select 2 answers.
A) Consent form is signed and 8. According to ICH GCP,
dated by the person which items require the
obtaining consent ‘favourable opinion’
B) Consent form is signed by (‘approval’) of an
the subject but dated by the ethics committee?
investigator Select 3 answers.
C) Consent form is signed and A) Protocol and any subsequent
dated by the subject amendments
D) A witness is always required
to sign the consent form B) Consent form and subject
information sheet
6. True or false? A log
identifying subjects recruited C) Investigator’s Brochure
to the study should be kept
by the investigator and a D) Case report form
photocopy of this should be
E) Recruitment methods (eg.
handed to the sponsor/
advertisements, posters)
monitor at the end of the
trial?
9. Select 3 options that apply to
7. A patient is considered by the use of equipment in a
the investigator to be suitable clinical trial.
for entry into the study.
However the patient is 6 A) It should be calibrated and
months too old, according to the results documented
the exclusion criteria in the
protocol. What should the B) It should be purchased
investigator do in order to specifically for the trial
fully comply with GCP and
regulatory requirements? C) The equipment should be
regularly maintained and
A) The investigator may obtain documented in a
permission from the sponsor maintenance log
to enter the patient
B) The investigator should not D) The equipment should be
enter the patient as it would available for use when it is
be a protocol violation required for trial purposes
26
E) Normal health service 11. Which essential documents

equipment may be used are only kept by the study
without calibration or site with no copy retained
maintenance by the sponsor?
Select 3 answers.
10. Whilst collecting samples
as part of a clinical trial, A) Signed consent forms
a subject faints. The B) Subject identification log
investigator is about to
take the timed 1-hour blood C) Final signed version of
sample from the subject. The protocol
event means that the sample
will now be taken 20 minutes D) Patient or subject files
late. What should happen? E) Product accountability
A) Take the sample and label it records
as a 1-hour sample, making
no file notes 12. True or false? The filing
cabinet containing the
B) Take the sample and make a essential documents for the
file note that it was collected trial should be left unlocked,
late, giving the reason why and in an area that allows
C) Miss the sample completely general access.
and take the next scheduled
sample, making no file notes Answers on page 54.
27
Chapter 3: Collecting and recording
trial data, including safety
monitoring and reporting
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).
Investigators should make sure that they clearly record a

subject's participation in a trial in their medical records
(patient files).
There are some basic rules for the collection of data in clinical trials.
These are often referred to as the ALCOA principles, whereby all data
should be attributable, legible, contemporaneous, original and
accurate. 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
• 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 the data (eg. a copy of the CRF pages).
29
Source documents
It is important that the sources of original data are kept so that CRF entries can
be checked and – if necessary – the trial can be re-created if CRFs are lost.
Source data and source documents are defined by ICH GCP (Sections
1.51 and 1.52, respectively) as follows.
• Source data. All information in original records and certified copies of
original records of clinical findings, observations, or other activities in a
clinical trial necessary for the reconstruction and evaluation of the trial.
Source data are contained in source documents (original records or
certified copies).
• Source documents. Original 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).
Source documents are the original documents, data and records

– effectively the first place where data are recorded.
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.
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.
30
Collecting and recording trial data, including safety monitoring and reporting
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.
The monitor will also compare the source documents with the data in the
CRFs. This process is called source data verification. The monitor will need
a period of ‘quiet time’ during his/her visit to undertake this process. The
investigator will be asked to explain and resolve any discrepancies
between the source data and the data recorded in the CRF.
To minimise further effort, investigators should ensure that

any data recorded in CRFs match those in original source
documents.
Breaches of protocol and GCP

If a member of the sponsor or investigator team becomes aware of a
breach of GCP or a violation of the study protocol, they should immediately
report this to their supervisor or the principal investigator.
The violation should usually be documented in the trial file, stating what
the violation was, how it was corrected and what steps were put into place
to prevent its recurrence. If an inspection is undertaken by
the regulatory authorities, the 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
of GCP and serious protocol violations to the UK
regulatory authority (the Medicines and Healthcare
products Regulatory Agency) in writing, within 7 days of discovery.
31
Correcting data in CRFs

If a change is required to data already recorded in a CRF, there is a very
precise way in which this must be undertaken. The sponsor’s trial monitors
will ensure that this process has been properly followed and will require
remedies to be made if it has not.
In order to change data already recorded in a CRF, the investigator simply
crosses through the incorrect data with a single line,
writes the new data alongside, and initials and
dates the change. For example:
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.
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)
32
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 safety of subjects in trials is the most important

consideration.
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
• 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.
As part of the essential safety monitoring process, investigators should
identify and record any untoward medical events that occur during the trial.
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
PvQP pharmacovigilance Qualified Person
33
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 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 italicised 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.
When recording an adverse event, 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 severity of any adverse event
• the outcome.
Adverse events should be followed 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
• the investigator could ask the 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?”
• the subject could be asked leading questions using an adverse events
checklist.
34
In addition to general observation, the 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 hospitalised 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.
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 hospitalisation or prolongation of existing
hospitalisation
• results in persistent or significant disability/incapacity, or
• is a congenital anomaly/birth defect.
35
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”.
36
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.
• If it is an adverse reaction, the sponsor will then assess whether or not
the adverse event was expected or unexpected. An unexpected reaction
is one in which the severity or frequency of the adverse reaction is not
consistent with the current product information (eg. as described in the
Investigator’s Brochure).
Adverse reactions that are serious and unexpected – in Europe these are
called suspected unexpected serious adverse reactions (SUSARs) – must
be expeditiously reported to the 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. This should be followed by as
SPONSOR
complete a report as possible within 8 additional calendar days.

This report must include an assessment of the importance and
implication of the findings, including relevant previous experience
with the same or similar medicinal products.
• Serious unexpected adverse
reactions that are not fatal or life-
threatening must be reported as
soon as possible, but no later
than 15 calendar days after first
knowledge by the sponsor.
37
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” (PvQP).
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 PvQP will co-ordinate this activity.
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
summarised, analysed and reported in the final study report.
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 investigational medicinal product, 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
hospitalises 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 hospitalised.
• 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.
38
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 computerised 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,
summarises 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.
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.
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 an unplanned interim analysis. If an interim analysis of the data
is planned before the study starts, this will be taken into account when
estimating the sample size and it will be documented in the statistical
analysis plan. Often, a Data Monitoring Committee (DMC) – consisting of a
group of experts independent of the study team – will be used to examine
data as the trial progresses, to determine whether a determined outcome
has been achieved. ICH guideline E9 (Statistical Principles for Clinical
Trials) is a useful source of further information on this subject.
39
End of study procedures

The regulatory authority that authorised the study and the relevant ethics
committee(s) should be informed when the trial has ended. In some
regions (eg. Europe) this has to be done within 90 days of the end of
the trial (often defined as last subject, last visit).
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.
The sponsor’s documents are collected together in
the Trial Master File (TMF), which should be located
in a safe and secure environment. Access to the
TMF should be restricted to authorised personnel.
After a trial has ended, the sponsor is responsible
for archiving the TMF.
Whilst many documents are common to both the
sponsor and investigator sites, some are unique to the study site (eg. the
enrolment log, signed consent forms and medical records such as patient
files). It is 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.
It is important that trial documents are archived in a safe
place at the end of the trial; however, reasonable
access is required. An index of the documents held in
an archive is essential.
Although there are guidelines on the
length of time for which trial documents
need to be kept (eg. ICH GCP
guidelines, Sections 5.5.7 – 5.5.12),
these vary from region to region. In
practice, a sponsor is unlikely to
destroy trial documentation. Sponsors will advise
investigators on the length of time to keep study documentation.
Investigators should expect this to be for a considerable period,
maybe 15 years or longer.
40
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 (eg. the UK Medicines and Healthcare products Regulatory Agency)
which also undertake inspections on behalf of the European Medicines
Agency and Japan’s regulatory body (the Japanese Ministry of Health, Labour
and Welfare).
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.
Due diligence is the key

Due diligence is required when performing clinical trials. A good rule to
remember is to document every aspect of the trial. If it is not written down and
filed away, it didn’t exist! Mistakes 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 organisation’s SOPs are adhered to.
GCP should not be considered a burden. Remember, it is in place to
protect the subjects who enter clinical trials and to make sure that the data
collected are useful and reliable.
41
Test your knowledge

1. True or false? The names of the monitor to make the
subjects should not be necessary change
recorded in case report forms
5. What best describes an
to preserve confidentiality.
adverse event?
2. When completing case report A) An unwanted medical
forms, investigators should occurrence in a trial subject
ensure that .... Select 3 that may or may not be
answers. caused by the study
A) There are no missing data medication
B) An unwanted medical
B) Data are recorded accurately
occurrence in a trial subject
C) Data are legible that is caused by the study
D) Incorrect data are hidden medication
using correcting fluids C) Any event that leads to the
E) All data are entered at the subject being hospitalised,
end of the study probably caused by the
study medication
3. What best describes the term
“source document”? 6. Which of the following would
be classified as a serious
A) The place where data are
adverse event?
recorded for the first time
A) Severe headache
B) Always the case report form experienced in the no
C) Always the patient file treatment run-in to the study,
pain killers prescribed
4. How should data be changed
B) Dizziness thought by the
in a case report form?
investigator to be possibly
A) Cross out the original entry related to study medication;
with a single line, enter the subject managed at home
new data alongside, date C) Sickness in a patient taking
and initial the change placebo, hospitalised for 2
B) Ensure that the original data days for rehydration therapy
are completely covered, D) Chest pain considered by
enter the new data alongside, the investigator to be related
date and initial the change to trial medication, treated in
C) Wait for the sponsor’s an emergency room but
monitor to review the case released from hospital after
report forms and then ask 2 hours
42
7. Which of the following 9. What is product

relationships to trial accountability?
medication would mean that A) The process of accounting
an adverse event is upgraded for every dose of medication
to an adverse reaction? in a clinical trial from its
More than one answer! manufacture to destruction
A) Definitely related to B) Tracking the amount of
treatment investigational product
B) Causal relationship cannot delivered to the investigator
be ruled out site
C) Considered unrelated to C) Records that indicate that
treatment by both the the investigational product
investigator and sponsor has been manufactured in
accordance with Good
D) Considered unrelated to
Manufacturing Practice
treatment by the sponsor but
possibly related to treatment
10. True or false? Investigational
by the investigator
medicinal product can still
be used to treat the
8. Which of the following would
investigator’s patients who
be classified as adverse
do not fulfil trial entry criteria
reactions? Select 2 answers.
as long as a case report
A) Severe headache form is completed.
experienced in the no
treatment run-in to the study, 11. Where should all specific
pain killers prescribed trial-related documentation
B) Dizziness thought by the be kept?
investigator to be possibly A) For the required period of
related to study medication; time in a Trial Master File
subject managed at home that is secure with limited
C) Sickness in a patient taking access
placebo, hospitalised for 2 B) For the required period of
days for rehydration therapy time in a Trial Master File
with unrestricted access to
D) Chest pain considered by
investigators and monitors
the investigator to be related
to trial medication, treated in C) In a secure third-party
an emergency room but storage facility with
released from hospital after access controlled by the
2 hours investigator
43
12. What are the potential B) Nothing at all; GCP is

consequences of failing to optional with no legal
adhere to Good Clinical requirement to comply
Practice guidelines when C) This may trigger an
performing a clinical trial on inspection by the regulatory
an investigational product? authorities
Select 2 answers.
D) In all cases the investigator
A) The trial results could be and sponsor will face
rejected and those involved criminal prosecution with
in the trial may face no chance of remedy
sanctions Answers on page 55.
44
Chapter 4: Essential study documentation
Many of the documents that should be part of the Trial Master File have
already been discussed. However, numerous other documents that are not
listed in Section 8 of the ICH GCP guidelines will also be generated and
will form part of the overall study file.
There are some basic rules for managing trial documents.
• A proper system of filing and storage is required, which might include
the use of filing cabinets. If this is the case, specific drawers should be
dedicated to the study. Avoid mixing 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!
• A log of all documents collected, and where they are stored, should be kept.
• Original documents are precious. Once collected, they should not be
removed from the files. Copies can be taken and these can be
used as working documents.
• Someone must be in charge of the trial files. The nominated person
should ensure that there is no unauthorised access to documents.
All trial files should be kept under lock and key.
• The location of the filing area is important. The documents must
be stored securely in an adequate and suitable space, free from
risk of loss, premature destruction and damage. For example,
thought must be given to how to protect the documents from fire,
floods, pests and other problems of nature. Inspectors will check
that the file location is suitable.
• When inspections occur, it is important that the requested
documents can be retrieved efficiently. Sometimes documents are
kept away from the office, even in a different country. Validated
copies will be acceptable in these circumstances.
• If documents are scanned or filmed, the copy must be validated to
ensure that it is a true reproduction of the original. Documents should
remain complete and legible throughout the required retention period.
45
Computerised systems
The increasing use of computers in clinical trials means that many of the
essential documents are in an electronic format. For example, data may be
entered directly onto a computer by the investigator. The data are then
transferred electronically to the sponsor’s computerised system. Laboratory
data may be sent directly to the sponsor’s system.
Guidelines on the use of computerised systems in clinical trials have been
published by the European Medicines Agency1 and the US Food and Drug
Administration2. Compliance with the current requirements helps to ensure
that any data collected using computerised systems are validated3.
There is an extensive list of requirements for a computerised system,
including the following:
• computerised systems used in trials should be identified and listed
• all critical systems should be validated and tested
• there should be operating procedures for the use of the systems, as well
as user manuals and suitable training
• equipment should be located in suitable places, where extraneous
factors cannot interfere with the system
• data should only be entered or amended by persons authorised to do so
• there should be suitable methods for deterring the unauthorised entry of
data, including the use of keys, pass cards, personal codes and
restricted access to computer terminals
• the system should be able to create a complete record of all entries and
amendments (an ‘audit trail’)
• for quality auditing purposes, it should be possible to obtain clear printed
copies of electronically stored data
• stored data should be checked for accessibility, durability and accuracy
• data should be backed-up at regular intervals
• back-up data should be stored for as long as necessary at a separate
and secure location.
1. The EMEA inspectors check the compliance of a computerised 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. All guidance is regularly updated to reflect current thinking, and requirements, such as those referred to
above, are changed.
46
Essential study documentation
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 may be used as checklists to determine the completeness of
documents in trial files.
The lists below are intended only for guidance – 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
✔ ✔ Investigator’s Brochure
✔ ✔ Signed protocol and amendments
✔ ✔ Subject information sheet and consent form
✔ ✔ Written instructions for subject
✔ ✔ Advertisement for recruitment
✔ ✔ Financial agreement with investigator
✔ Contract research organisation (CRO) agreement
(if any)
✔ ✔ Insurance statement
✔ ✔ Investigator agreement
✔ ✔ Independent ethics committee (IEC)/institutional
review board (IRB) opinion on final protocol,
information sheets, consent form, recruitment
advertisements, etc
✔ ✔ IEC/IRB composition
✔ ✔ Agreement with pharmacy
✔ ✔ Regulatory opinion notification
✔ ✔ CVs of relevant study site staff
✔ ✔ CV of principal investigator
✔ ✔ Reference ranges for laboratory evaluations
✔ ✔ Reference ranges for study tests
✔ ✔ Laboratory procedures and quality assurance (QA)
records
47
✔ ✔ Laboratory certification/accreditation
✔ Sample of label (investigational medicinal product;
IMP)
✔ ✔ Handling instructions (IMP)
✔ ✔ Shipping records (IMP)
✔ (✔) Certificate of analysis (IMP)
✔ ✔ Signing off IMP by Qualified Person
✔ ✔ Decoding procedures
✔ Master randomisation list (blinded)
✔ Pre-trial monitoring report (of site)
✔ ✔ Study initiation report
✔ ✔ Investigator’s study personnel log
✔ ✔ Manufacturing/import authorisation for IMPs (if
required)
✔ ✔ Documentation relating to any Data Monitoring
Committee
✔ ✔ Final case report form
✔ ✔ Documents relevant to investigational new drug
(IND) applications (eg. Form FDA 1572), if any
✔ Statistical analysis plan
✔ Blank case report form (CRF)
During study documents

✔ ✔ Investigator’s Brochure updates
✔ ✔ Amendments to protocol, subject information sheet,
consent form, CRF updates, advertisements
✔ ✔ IEC/IRB opinion for updated documents
✔ ✔ Documents relating to applications for amendment
to protocol
✔ ✔ Regulatory opinion of amendments
✔ ✔ IEC/IRB notification of continuing review
✔ ✔ CVs of new staff
48
✔ ✔ Updates to reference ranges
✔ ✔ Updates to laboratory procedures
✔ ✔ Records of product shipment to investigator
✔ (✔) Certificates of analysis for new IMPs
✔ ✔ Signing off new IMP by QP
✔ Monitoring visit reports
✔ ✔ Log of monitoring visits made to site
✔ ✔ Letters and other records of communication with
study site
✔ ✔ Completed CRF pages (sponsor – original;
investigator – copy)
✔ ✔ Documented changes to CRFs
✔ ✔ Signature sheet (those making CRF
entries/corrections)
✔ ✔ Notifications of serious adverse events (investigator
to sponsor)
✔ (✔) Notifications of serious adverse reactions (sponsor
to authorities)
✔ ✔ Safety information provided to investigators
✔ ✔ Safety updates to competent authorities
✔ ✔ Safety information provided to IEC/IRB
✔ ✔ Annual report to IEC/IRB
✔ ✔ Product accountability at study site
✔ ✔ Record of retained samples and body fluids/tissues
✔ ✔ Updates to investigator’s study personnel log
✔ ✔ Documentation and explanation by investigator of
any protocol deviation
✔ ✔ Communication from monitor/sponsor to
investigator on protocol deviations
✔ Code-break envelopes
49
Post-study documents
✔ ✔ Final product accountability at study site
✔ ✔ Documentation relating to product destruction
✔ Audit certificate(s)
✔ Final study close-out report
✔ Treatment allocation and master decoding
information
✔ ✔ Final clinical study report
✔ ✔ Notification to authorities of end of trial
✔ ✔ Notifications to IEC/IRB about study end
✔ ✔ List of archived documents and location (archive
index/log)
✔ ✔ List of Standard Operating Procedures and
versions used during trial
✔ ✔ Completed list of sponsor/CRO personnel involved
in study
✔ ✔ Details of any transfer of ownership of study-related
documentation
✔ ✔ Identification of archivist(s)
✔ ✔ Written information to investigator regarding record
retention
Investigator site only

✔ Signed consent forms
✔ Source documents, eg. patient files
✔ Subject identification list
✔ Subject screening log
✔ Subject enrolment log
✔ Copies of completed CRF pages
✔ Documented changes to CRFs (copy)
✔ Subject consent to allow viewing by third parties of
patient files
50
✔ Authority of subject to contact primary care
physician
✔ Final report by investigator to IEC/IRB/regulatory
authority (where required/applicable)
✔ Consent of subject to process and transfer personal
data
Sponsor general files

✔ List of SOPs and versions used
✔ Internal meeting minutes
✔ CVs of sponsor trial staff
✔ Training records of sponsor trial staff
✔ Study audit reports (in QA files not general Trial
Master File)
✔ Correspondence with regulatory authorities
✔ Meetings with regulatory authorities
✔ Scientific advice
✔ Documentation relating to inspections
✔ Out-of-date/draft versions of trial documentation
(eg. protocol)
✔ Master randomisation list (unblinded)
✔ Trial registration documentation, eg. EudraCT,
Clinical Trial Authorisation/IND application
✔ Manufacturing and/or import authorisation
✔ 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.
51
Additional guidance for European studies

A useful guideline for documentation requirements in Europe is contained
in EudraLex Volume 10, Clinical Trials Guidelines, Chapter V. The guideline
– entitled ‘Recommendation on the Content of the Trial Master File and
Archiving’ – contains a list of minimum document requirements as well
as guidance on the quality of essential documents, media to be used,
storage conditions, and the retention and destruction of essential
documents. The document is available from
<http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol10_en.htm>.
52
Answers to tests
all trial processes to ensure

compliance with regulations
Chapter 1
1. What is Good Clinical and the organisation’s policies
Practice?
A) A quality standard applied to 7. What impact does GCP
trials in order to improve implementation have on
subject protection and the clinical trials?
quality of data collected in A) Facilitates better subject
the trial protection
B) Facilitates collection of
2. Who is affected by GCP? credible data
A) Sponsors, investigators, C) Facilitates better study
ethics committees documentation
3. What is meant by the term ICH? 8. True or false? Available
C) International Conference on non-clinical and clinical
Harmonisation information should be
adequate to support the
4. Which countries/regions proposed clinical trial.
came together to develop the
True
ICH process?
A) Japan 9. True or false? The rights,
B) USA safety, and well-being of the
C) Europe trial subjects are the most
important considerations but
5. Which accepted code of need not prevail over interests
practice describes the of science and society.
investigator’s ethical False
principles applicable in
global clinical trials? 10. True or false? All clinical
A) Declaration of Helsinki trial information should be
recorded, handled, and stored
6. What are Standard Operating in a way that allows
Procedures (SOPs)? its accurate reporting,
A) Documented procedures interpretation and verification.
and systems that describe True
53
11. In addition to following A) Obtain written informed

GCP guidelines, what other consent from each subject
requirements should a study before they undertake any
sponsor always adhere to? study-related procedures
A) National legislation of the 5. Which of the following are
country where the trial is required to ensure consent is
being carried out correctly documented?
B) Sponsor’s own Standard
Operating Procedures (SOPs) A) Consent form is signed and
dated by the person
obtaining consent
Chapter 2 C) Consent form is signed and
dated by the subject
1. According to GCP, how
should the investigator show 6. True or false? A log
that he/she has the appro- identifying subjects recruited
priate qualifications and to the study should be kept
experience to do the study? by the investigator and a
A) Providing an up-to-date, photocopy of this should be
signed and dated CV handed to the sponsor/
monitor at the end of the
2. True or false? Trial sponsors trial?
are required to have False
insurance to cover the
compensation of trial subjects 7. A patient is considered by
in the event of product-related the investigator to be suitable
damage and also to indemnify for entry into the study.
investigators. However the patient is 6
True months too old, according to
the exclusion criteria in the
3. How should a researcher protocol. What should the
become familiar with the investigator do in order to
investigational product to be fully comply with GCP and
used in a clinical trial? regulatory requirements?
B) Obtaining and reading the B) The investigator should not
up-to-date Investigator’s enter the patient as it would
Brochure from the sponsor be a protocol violation
of the trial
8. According to ICH GCP, which
4. How does GCP require the items require the ‘favourable
informed consent of a trial opinion’ (‘approval’) of an
subject to be obtained? ethics committee?
54
Answers to tests
A) Protocol and any D) Patient or subject files

subsequent amendments
12. True or false? The filing
B) Consent form and subject
cabinet containing the
information sheet
essential documents for the
E) Recruitment methods (eg. trial should be left unlocked,
advertisements, posters) and in an area that allows
general access.
9. Select 3 options that apply to
the use of equipment in a False
clinical trial.
A) It should be calibrated and Chapter 3
the results documented
1. True or false? The names
C) The equipment should be of subjects should not be
regularly maintained and recorded in case report forms
documented in a to preserve confidentiality.
maintenance log
True
D) The equipment should be
available for use when it is 2. When completing case report
required for trial purposes forms, investigators should
ensure that ....
10. Whilst collecting samples as A) There are no missing data
part of a clinical trial, a
subject faints. The B) Data are recorded accurately
investigator is about to take C) Data are legible
the timed 1-hour blood
3. What best describes the term
sample from the subject.
“source document”?
The event means that the
sample will now be taken A) The place where data are
20 minutes late. What should recorded for the first time
happen? 4. How should data be changed
B) Take the sample and make in a case report form?
a file note that it was A) Cross out the original entry
collected late, giving the with a single line, enter the
reason why new data alongside, date
11. Which essential documents and initial the change
are only kept by the study 5. What best describes an
site with no copy retained by adverse event?
the sponsor? A) An unwanted medical
A) Signed consent forms occurrence in a trial subject
B) Subject identification log that may or may not be
55
caused by the study 9. What is product

medication accountability?
6. Which of the following would A) The process of accounting
be classified as a serious for every dose of medication
adverse event? in a clinical trial from its
manufacture to destruction
C) Sickness in a patient taking
placebo, hospitalised for 2 10. True or false? Investigational
days for rehydration therapy medicinal product can still
be used to treat the
7. Which of the following
investigator’s patients
relationships to trial
who do not fulfil trial entry
medication would mean that
criteria as long as a case
an adverse event is upgraded
report form is completed.
to an adverse reaction?
False
A) Definitely related to
treatment 11. Where should all specific
B) Causal relationship cannot trial-related documentation
be ruled out be kept?
D) Considered unrelated to A) For the required period of
treatment by the sponsor but time in a Trial Master File
possibly related to treatment that is secure with limited
by the investigator access
8. Which of the following 12. What are the potential
would be classified as consequences of failing to
adverse reactions? adhere to Good Clinical
B) Dizziness thought by the Practice guidelines when
investigator to be possibly performing a clinical trial on
related to study medication; an investigational product?
subject managed at home A) The trial results could be
D) Chest pain considered by rejected and those involved
the investigator to be related in the trial may face
to trial medication, treated in sanctions
an emergency room but C) This may trigger an
released from hospital after inspection by the regulatory
2 hours authorities
56
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Essential GCP by Professor David Hutchinson

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Essential GCP by Professor David Hutchinson

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Essential

Published by Canary Ltd, PO Box 9, Guildford, Surrey GU3 2WZ, UK

Production editor: Sharon Jordan

Chapter 2: General GCP responsibilities and 13

Chapter 3: Collecting and recording trial data, 29

Chapter 4: Essential study documentation 45

Professor David Hutchinson

Factors affecting clinical trials

Other regulations and guidelines

In Europe, directives must be passed into Member States’

The regulations in the USA – published in the Federal Register and

Europe accounts for about one-third of patients recruited

Who does GCP affect?

Where did GCP start?

• pharmaceutical industry representatives: European Federation of

Summary of ICH products

ICH GCP guidelines

• All clinical trial information should be recorded, handled, and stored in a

Compliance with GCP

Documenting GCP compliance

If it is not documented, it didn’t happen!

The minimum content of the study file at both

Someone should be appointed to manage the study files.

Test your knowledge

B) Facilitates collection of recorded, handled, and

The investigator and study site

The investigator must have time to undertake the

Log of study personnel

Addressing the risks of trials

Compensation should be paid

Even if an adverse reaction causing the injury was foreseeable or

The information in the Investigator's Brochure should be

If the product is already marketed, information about the medicine can be

The study protocol

Recruiting trial subjects

Subject enrolment log

Signing consent forms

Updates to consent forms

Test your knowledge

5. Which of the following are C) The investigator can amend

E) Normal health service 11. Which essential documents

Data collection in clinical trials

Investigators should make sure that they clearly record a

Source documents are the original documents, data and records

Monitoring and source data verification

To minimise further effort, investigators should ensure that

Breaches of protocol and GCP

Correcting data in CRFs

Why monitor? The purpose of trial monitoring is to verify that

Safety monitoring, recording and

The safety of subjects in trials is the most important

The ICH E2 guidelines (see <www.ich.org>) provide more detail on the

Commonly used safety abbreviations

In addition to general observation, the most commonly used method to

Examples of adverse events:

Serious adverse events

The term “life-threatening” in the definition of serious adverse event refers

Expedited reporting of serious adverse reactions

complete a report as possible within 8 additional calendar days.

Managing other safety reports

Example of a pharmacovigilance decision-making

Analysis and reporting of trial data

In a blinded study, the study code is broken when the final

It is very important that no unplanned data analyses are undertaken whilst