results, the whole process should be transparent,
that is everything must be documented so that an
external reviewer may verify that the research was
actually conducted as reported by the researchers.
The general regulatory framework
for GCP
The regulatory framework for compliance with
research procedures has essentially developed on
an international basis only in the last two decades,
except for the United States where rules were
first established in the 1930s. Today, countries in
the European Union, other countries in Europe (e.g.
Switzerland) and Japan have regulations on GCP.
Othercountries have regulations controlling clinical
studies, with guidelines on GCP, such as Australia
and Canada. In the 1990s, an attempt was made to
harmonizeGCPrequirementsintheformoftheICH
GCP document which has since been adapted in
regulation by many countries. Some countries
have no guidelines or regulations, but guidance for
researchershasbeenprovidedbyoragnizationssuch
as the Council for the International Oragnizations of
Medical Sciences (CIOMS) and the World Health
Organization (WHO). (A brief list of existing reg-
ulations and guidelines ispresented at the end of this
chapter.) Regulatory authority review and/or
approval is usually necessary in all countries before,
during and after clinical studies. With the advent of
the EU Clinical Trials Directive, compliance with
the principles of GCP is now a legal obligation in
Europe for all trials of investigational medicinal
products. Further, it is now a legal requirement in
Europe for these investigational medicinal products
to be manufactured, handled and stored to the stan-
dards of Good Manufacturing Practice (GMP) in
order to prevent exposure of subjects to defective
medicines.
In the past few years, there has been increasing
interest in regulatory inspection of GCP compli-
ance to ensure validity of the data and protection of
study subjects and to compare the practices and
procedures of the investigator and the sponsor/
contract research organization (CRO) with the
commitment made in the application to undertake
a study. Although inspection has been a regulatory
requirement in the United States for many years,
inspectorates have only just started in countries
such as Austria, Denmark, France, Finland, Ger-
many, Japan, The Netherlands, Norway and Swe-
den. There are problems in finding good inspectors,
in deciding on the final standards for inspections
and in imposing sanctions for noncompliance. An
interesting recent development has been the initia-
tion of inspections in Europe by the central regu-
latory authority, the European Medicines Agency
(EMEA). Regulation of compliance with require-
ments by ethics committees is also developing in
some parts of theworld (e.g. France and Denmark).
To date, the US Food and Drug Administration
(FDA) is the only authority that is actively check-
ing on the activities of institutional review boards
(IRBs) by inspection and licensing.
For noncompliance with regulations, only the
United States has imposed serious sanctions to
date. The ‘blacklist’ (list of all investigators who
have been found to be noncompliant and were
barred from clinical research for FDA submis-
sions) is publicly available through freedom of
information rules. The United States has vast
experience (thousands of inspections) compared
to the handful of inspections in other countries.
Within a research organization, other indepen-
dent review, auditing, is undertaken internally to
check on compliance with standards and basically
to pre-empt the inspectors. Auditing may be con-
ducted at any time during a clinical study to ensure
continued compliance with GCP. Almost all
aspects of GCP could be audited. Auditing, by
definition, must be undertaken by personnel who
are independent of the research being audited.12.2 Setting up clinical studies
To ensure that the standards for clinical research
are established before studies begin and to check
on compliance with those standards, many funda-
mental systems and processes must be defined by
study sponsors and CROs. These are outlined in
Table 12.1.
The sponsor/CRO has a duty to place a study
safely. That is, the sponsor (or the delegated CRO)
must assess and choose a site where study subjects140 CH12 GOOD CLINICAL PRACTICES