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Facing the Challenges of the European Clinical Trials Directive – The EORTC Perspective
Commission 6th and 7th Framework Programmes, will assess whether
Figure 1: EU Member States’ National Legislation Implementing
the current Directive can be amended or if new legislation is required.
the European Clinical Trials Directive 2001/20/EC
Application of the EU Clinical Trials Directive –
AT FI SE
Benefit or Burden? 4 legal acts
CZ ETO HU LT
Major bottlenecks and obstacles have emerged for academic
DK IE UK
2 application sets
LV PL SL SV
4 legal acts
1 guidance
researchers when applying the EU CTD. First, due to its legal nature,
8 legal acts
4 application sets
15 application sets
transposition of the Directive imposed a complex new legal landscape
8 guidances
1 guidance
consisting of 27 frameworks at the EU national level. Gaining access to
domestic legislation, corresponding updates and maintaining familiarity
BE DE FR IT LU NL BU RO
11 legal acts 2 legal acts
with each new regulation, decree or ordinance is a challenge in itself.
25 application sets 6 application sets
An overview of the current European legal framework, legislation,
10 guidances 1 guidance
regulations and guidelines related to the conduct of clinical trials with
medicinal products is shown in Figure 1. The amount of information ES PT
CV GR MT
2 legal acts
3 legal acts
that one needs to consider when planning and conducting clinical trials
3 application sets
4 application sets
in Europe is immediately striking and reflects the diversity of national
1 guidance
7 guidances
implementations of the Directive. Although the Directive set out to
introduce a single set of principles and procedures, EU Member States
have implemented it in different ways. Countries differ notably in their
AT = Austria; BE = Belgium; BU = Bulgaria; CZ = Czech Republic; CY = Cyprus;
interpretation of the sponsorship rules, the complexity of the
DE = Germany; DK = Denmark; ES = Spain; ETO = Estonia; FI = Finland; FR = France;
GR = Greece; HU = Hungary; IE = Ireland; IT = Italy; LT = Lithuania; LU = Luxemburg;
procedures for ethics approval and the level of detail required for drug
LV = Latvia; NL = The Netherlands; PL = Poland; MT = Malta; PT = Portugal; RO = Romania;
safety reporting. Harmonisation is still a distant reality.
SE = Sweden; SL = Slovenia; SV = Slovakia; UK = The United Kingdom.
Figure 2: European Organisation for Research and Treatment of
Second, the Clinical Trials Directive applies to “the conduct of clinical
Cancer Global Insurance Costs 1996–2006
trials, including multicentre trials, on human subjects involving
medicinal products”.
9
The EU CTD, issued by the Directorate
700
Enterprise, was written in the context of interventional trials testing
600
investigational medicinal products (IMPs) largely intended for inclusion
in registration dossiers compiled by the pharmaceutical industry. It
500
failed to define the legal system that would apply to non-
c
rease
400
interventional trials, interventional trials not testing a drug or trials c
ost in
300
using a standard drug treatment but focusing on other therapeutic c
ent
modalities such as radiation therapy or surgery. Further difficulties
P
er
200
arise when considering complex research projects that evaluate
100
multimodality treatments involving radiotherapy, surgery or
0
combination surgery–radiotherapy. An unintended consequence of the 1996 2000 2002 2005 2006
EU CTD was the indiscriminate application of these rules to other types
Year
of clinical study.
10
Cost in 1996 Increase in costs
Third, the overall costs of conducting cancer clinical trials have increased differences in fees levied on non-commercial sponsors range from €0
substantially under the EU CTD. The global cost of EORTC insurance to €2,500 for an initial ethics committee application and from €0 to
coverage multiplied approximately five-fold between 1996 and 2006, €1,000 when submitting a substantial trial amendment. A number of
with increases ranging from 22 up to 128% (see Figure 2). Prior to the Member States agreed to a waiver for non-commercial sponsors
EU CTD, the EORTC insured its clinical trials with an annual global policy through the ‘legal recognition’ of academic research.
12
Likewise, fees
covering all participating countries. Today, national variability in the type paid to Competent Authorities range from €0 to €4,000 for an initial
of policy required (i.e. fault or no-fault) and the ceiling of costs and/or application and from €0 to €1,500 for a substantial amendment with
duration of coverage force the EORTC to hold different insurance waivers for non-commercial sponsors.
13
Some Ethics Committees, as in
policies to comply with all territories and regulations.
11
The annual the case of Germany, also charge for the review of suspected
insurance policy covers a said territory under which a given number of unexpected serious adverse reactions (SUSARs).
patients are insured per year for a specific Member State regardless
of the number of clinical trials activated. To date, the EORTC has The so-called ‘free-of-charge’ supply of IMPs, as defined in Article 2(d)
contracted only six annual policies. The second is the individual of the Directive, pushes costs even higher. National divergences exist
insurance policy, which is protocol-based for a given country. Thirteen in the interpretation of this concept. The classification of a medicinal
countries were insured under this type of policy in 2006. product as an IMP has important financial implications for the Sponsor.
Article 19 of the Directive stipulates that unless Member States have
Fees paid to Competent Authorities and/or Ethics Committees for established precise conditions for exceptional circumstances, the
submitting a Clinical Trials Application also contribute to the rising Sponsor must provide, free of charge, IMPs and any device(s) used for
costs of academic clinical research under the Directive. National their administration. This disposition does not apply to non-IMPs and
EUROPEAN ONCOLOGY 15
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