The importance of Good Clinical Practice guidelines and its role in clinical trials
Department of Biomedical Imaging, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
Good Clinical Practice (GCP) is an international ethical
and scientific quality standard for the design, conduct, performance,
monitoring, auditing, recording, analyses and reporting of clinical trials. It
also serves to protect the rights, integrity and confidentiality of trial
subjects. It is very important to understand the background of the formation of
the ICH-GCP guidelines as this, in itself, explains the reasons and the need
for doing so. In this paper, we address the historical background and the
events that led up to the formation of these guidelines. Today, the ICH-GCP
guidelines are used in clinical trials throughout the globe with the main aim
of protecting and preserving human rights. � 2008 Biomedical Imaging and
Intervention Journal. All rights reserved.
Keywords: Clinical practice, international, ethical,
Good Clinical Practice (GCP) is an international ethical
and scientific quality standard for the design, conduct, performance,
monitoring, auditing, recording, analyses and reporting of clinical trials. GCP
provides assurance that the data and reported results are credible and
accurate, and that the rights, integrity and confidentiality of trial subjects
are respected and protected . It was finalised in 1996 and became effective
in 1997, but was not enforced by law at that time. The Medicines for Human Use
(Clinical Trials) Regulations 2004 and the European Union (EU) Directive on
Good Clinical Practice changed the world perspective , and compliance with GCP
is now a legal obligation in the UK/Europe for all trials involving the
investigation of medicinal products .
It is very important to understand the background of the
formation of the ICH-GCP guidelines as this, in itself, explains the reasons
and the need for doing so (Table 1). The concept of the 'good physician' dates
back to the ancient world and it is evidenced by the Hippocratic Oath (460 BC).
In the United States, the first landmark in the regulation of drugs was the
Food and Drugs Act of 1906. This was a result of harmful and lethal drugs that
could be bought across the counter just like any other consumer product. Some
examples are 'Grandma's Secret' and 'Kopp's Baby's Friend' which contained
large doses of morphine, as well as 'Dr King's Consumption Cure' and 'Dr Bull's
Cough Syrup' which contained morphine and chloroform . In 1938, the Federal
Food, Drug and Cosmetic Act was enacted by the Food and Drug Administration
(FDA) and for the first time, manufacturers were required to test drugs for
safety and present the evidence of safety testing to the FDA prior to marketing
In 1947, the Nuremberg Code was created as a result of the
unethical and horrific experiments carried out during World War II at Nazi war
camps by German physicians, who were subsequently tried and charged at the
Nuremberg Military Tribunal. This code states the need for a scientific basis
in research on human subjects and voluntary consent and protection of
participants [4,5]. The Universal Declaration of Human Rights (December 10th
1948) was also adopted and proclaimed by the United Nations after the
atrocities of World War II and it further reiterated the human factor involved
in medical experiments.
In 1964, the Declaration of Helsinki was developed by the
World Medical Association, forming the basis for the ethical principles that
underlie the ICH-GCP guidelines we have today. The focus of this declaration is
the protection of the rights of human subjects and this is clear in its
�The World Medical Association has developed the
Declaration of Helsinki as a statement of ethical principles to provide
guidance to physicians and other participants in medical research involving
human subjects. It is the duty of the physician to promote and safeguard the
health of the people. The physician's knowledge and conscience are dedicated to
the fulfilment of this duty��
In 1962 the world was once again shocked by the severe
foetal limb deformities linked to the use of maternal thalidomide. In fact this
drug reaction was only discovered after 10,000 infants were born in over 20
countries worldwide. In response to this, the Kefauver-Harris Amendments were
passed which required the FDA to evaluate all new drugs for safety and efficacy
Another important milestone in the formation of the
ICH-GCP guidelines was The Belmont Report which was issued in April 1979 by the
National Commission for Protection of Human Subjects of Biomedical and
Behavioural Research . The principles of this report are as follows:
- Respect for Persons: This principle acknowledges the dignity and
freedom of every person. It requires obtaining informed consent from research subjects
(or their legally authorised representatives)
- Beneficence: This principle requires that researchers maximise
benefits and minimise harms associated with research. Research-related risks
must be reasonable in light of the expected benefits.
- Justice: This principle requires equitable selection and
recruitment and fair treatment of research subjects.
In 1982, the World Health Organization (WHO) and the
Council for International Organizations of Medical Sciences (CIOMS) issued a
document entitled 'International Guidelines for Biomedical Research Involving
Human Subjects'. This document was released to help developing countries apply
the principles of the Declaration of Helsinki and the Nuremberg Code .
Worldwide, many organisations and committees issued various documents and
guidelines on the same issue, and a decision was taken to consolidate all these
guidelines into one universal guideline to be used globally.
In an effort to overcome international GCP inconsistencies
throughout the countries, the International Conference for Harmonisation of
Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)
issued the ICH Guidelines: Topic E6 Guideline for GCP. This guideline was
approved on 17 July 1996 and implemented for clinical trials from 17 January
1997. The participants of these guidelines were representatives of authorities
and pharmaceutical companies from the EU, Japan and the United States as well as those of Australia, Canada, the Nordic countries and WHO .
The ICH-GCP is a harmonised standard that protects the
rights, safety and welfare of human subjects, minimises human exposure to
investigational products, improves quality of data, speeds up marketing of new
drugs and decreases the cost to sponsors and to the public. Compliance with
this standard provides public assurance that the rights, safety and well-being
of trial subjects are protected and consistent with the principles of the
Declaration of Helsinki, and that the clinical trial data is credible . A
historical background of the reasons and the importance of GCP is summarised in
There are 13 core principles of ICH-GCP and they are as
- Clinical trials should be conducted in accordance with 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 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 interest of science and
- The available non-clinical and clinical information on an
investigational product should be adequate to support the proposed clinical
- Clinical trials should be scientifically sound, and described in clear,
- 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.
- 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.
These principles are self-explanatory and, when summarised,
All clinical trials should be conducted in accordance with
ethical principles, sound scientific evidence and clear detailed protocols. The
benefits of conducting trials should outweigh the risks. The rights, safety and
well-being of trial participants are of paramount importance and these should
be preserved by obtaining informed consent and maintaining confidentiality. The
care must be given by appropriately qualified personnel with adequate
experience. Records should be easily accessible and retrievable for accurate
reporting, verification and interpretation. Investigational products should be
manufactured according to Good Manufacturing Practice (8).
It is also important to mention the participants of GCP in
clinical trials and their respective responsibilities. These are summarised in
GCP in the Asia Pacific Region
Since the conception of the ICH-GCP guidelines, many
countries in the Asia-Pacific region realised the need to formulate guidelines
of their own based on the framework of the original guidelines . This is
clearly seen in Table 4 that tabulates the adoption of GCP in our country and
In Malaysia, similar guidelines were formulated in the
wake of greater demand by the pharmaceutical industry to conduct clinical
trials in the country. The Malaysian Guidelines for GCP was first published in
October 1999 and the second edition was released in January 2004. The guideline
adopts the basic principle outlined by the International Committee on
Harmonization of Good Clinical Practice (ICH-GCP) with some modifications to
suit local requirements [1,7].
The importance of GCP lies in the question 'why' and 'how'
GCP trials came about. To know the answer to this, we have to look to the
historical background that led to the formulation of GCP guidelines in the
United States and Europe and also to the formation of the ICH. The events that
led up to the culmination of the ICH-GCP guidelines brought forth public
awareness that there was a need to control and regulate clinical trials dealing
with drugs and human subjects. The violation of human rights played a large
role and that is why the Declaration of Helsinki and The Nuremberg Code remain
as the framework of the present guidelines. The ICH-GCP guidelines are
therefore considered the 'bible' of clinical trials, and have become a global
law which safeguards humanity as we know it today.
Table 1 Historical background of GCP
Table 4 GCP Adoption in the Asia Pacific Region
Malaysian Guidelines for Good Clinical Practice. 2nd edition. Ministry of Health Malaysia, 2004.
Imperial College Clinical Research Governance Office. Good Clinical Practice [Web Page]. 2007; Available at http://www.imperial.ac.uk/clinicalresearchoffice.
Otte A et al. Good Clinical Practice: Historical background and key aspects. 2005; 26:563-74.
Office of Human Subjects Research. The Nuremberg Code [Web Page]. 1949; Available at http://ohsr.od.nih.gov/guidelines/nuremberg.
The Doctors Trial (the Medical Case of the Subsequent Nuremberg Proceedings) [Web Page]. Available at http://www.ushmm.org/research/doctors/Nuremberg_Code.htm.
The World Medical Association. Declaration of Helsinki [Web Page]. 2004; Available at http://www.wma.net/e/policy/b3.htm.
Vadivale M. ICH-GCP Guidelines for Clinical Trials. Berita MMA. 1999: 7 (29).
European Medicines Agency. ICH Harmonised Tripartite Guideline E6: Note for Guidance on Good Clinical Practice (PMP/ICH/135/95). London: European Medicines Agency, 2002.
|Received 6 November 2007; received in revised form 25
December 2007, accepted 11 January 2008
Correspondence: Department of Biomedical Imaging, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia. Tel.: +603-79492069; Fax: +603-79581973; E-mail: email@example.com (Anushya Vijayananthan).
Please cite as: Vijayananthan A, Nawawi O,
The importance of Good Clinical Practice guidelines and its role in clinical trials , Biomed Imaging Interv J 2008; 4(1):e5
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