Principles and Practice of Pharmaceutical Medicine

can usefully provide independent clinical expertise
on products under evaluation by the CHMP with-
out, of course, removing the final responsibility for
the scientific opinion with the latter. Such TAGs
(currently in oncology, infective diseases and diag-
nostic agents) have core members who are
appointed by the CHMP, and can appointad hoc
external experts, when necessary.

34.6 Current European regulatory

practice

Clinical trials: Directive 2001/20

This Directive was to be implemented by all EU
MS by May 1, 2004. As a result, approval of
clinical trials is no longer based on the former
uneven laws of individual MS, but rather on how
each state has implemented this Directive, which is
much more uniform.
The scope of Directive 2001/20 is broad. All
clinical studies of medicinal products involving
human subjects (both patients and normal volun-
teers) fall within its remit, unless the trial is merely
observational and noninterventional. This applies
equally to the pharmaceutical industry, academia,
government research institutes and all others.
The Directive

sets standards for the protection of study sub-
jects, including especially vulnerable groups
such as children and incapacitated adults;

requires every MS to have a central governing
body that oversees ethics committees;

mandates that national licensing authorities must
now affirmatively permit clinical trial initiation;

prescribes standards for the manufacture, import
and labeling of all investigational medicinal pro-
ducts (IMPs);

establishes an inspection system to ensure com-
pliance with good manufacturing practices
(GMP) and good clinical practices (GCP);

focuses particularly on the safety monitoring of

participating subjects in trials and sets out pro-

cedures for doing so;

mandates safety reporting to a pan-European

pharmacovigilance database.

The National Competent Authority (NCA) in each

MS (e.g. the BfArM in Germany or the MHRA in

the United Kingdom) reviews proposed clinical

trials within their jurisdictions; if satisfied with

the information provided, then the NCA notifies

the study sponsor that it has no grounds for objec-

tion. The Directive sets a timeline for review of up

to 60 days for most trials, as well as for substantial

protocol amendments, although there are options to

extend this timeline under special circumstances,

such as for gene therapy studies, where there is no

time limit at all. The authorization granted by the

regulatory authority (RA) – a clinical trial author-

ization (CTA) – is issued study-by-study, with affir-

mative notifications being needed for every protocol

separately; this is an important difference from the

IND regulations in the United States.

The Clinical Trials Directive requires the inte-

gration of the GCP guidelines into the national law

of all MS (which had not been the case in some MS

before May 2004). Local regulatory authorities

now carry the burden of inspecting for compliance

with both GCP and the GMP guidelines for inves-

tigational drugs. Inspections take place at both

sponsor’s facilities and clinical trial sites.

All research involving human subjects (apart

from wholly noninterventional, observational stu-

dies), including academic research and Clinical

Pharmacology studies in healthy volunteers, fall

within the scope of the Directive. The latter,

hitherto, had a much lighter administrative burden

or even no regulatory oversight at all in some MS.

The need now to provide the same amount of infor-

mation and be subject to RA review just as much as

later phase clinical research has led to some com-

plaints, especially in the academic community.

The European Commission issued a set of

detailed guidelines on the requirements and format

of the CTA application for use by NCAs and ethics

committees, as well as templates for application

forms.Directive2001/20 has alsoadded asmall but

448 CH34 MEDICINES REGULATION IN THE EUROPEAN UNION