Faiz Kermani
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When the European Clinical Trials Directive (2001/20/EC) was introduced in 2004, it fundamentally changed the way in which
clinical trials were conducted across the EU. The Clinical Trials Directive had a number of different aims, but key among
these were a desire to provide a more harmonised structure for clinical trial regulations across the EU and to ensure that
patient safety was specifically addressed in EU legislation.1–3 Optimists predicted that as individual countries defined their national legislation to account for the Clinical Trials Directive,
advantages would emerge from having standardised processes.1
The Directive in practice
Efforts to implement the Clinical Trials Directive soon revealed the complexities of developing a pan-European system to the
satisfaction of multiple parties in different member states. For example, despite widespread publicity, some EU member states
had not implemented (such as the Netherlands) or only partially implemented (such as France) the provisions of the Directive
6 months after the deadline.1 To try and improve this situation, the EU Heads of Medicines Agencies (HMA) had established the Clinical Trials Facilitation
Group (CTFG). This group attempted to coordinate the implementation of the Clinical Trials Directive across the member states
at an operational level and further improve harmonisation of relevant regulatory requirements.4
The delay in implementing the Clinical Trials Directive caused numerous complications for companies operating in Europe, who
were already finding the new processes unclear. For companies, the introduction of the Directive was problematic because they
had to adjust to a completely new system for conducting clinical trials, which required additional regulatory support to keep
up with changes because of legislation in different countries.1 Advance planning was also needed for selecting and auditing manufacturers, and sponsors had to ensure that they had a presence
in the European Economic Area as they would be liable for any breaches of the Clinical Trials Directive.2 For companies without such a base, a local CRO could serve this function.2
Aside from companies, academic researchers running clinical trials were also affected. Many researchers, particularly those
in the oncology field, soon objected to the Clinical Trials Directive because it added a new layer of bureaucracy to their
work for very little identifiable reward.3 In 2005, The European Organization for Research and Treatment of Cancer (EORTC), the largest independent European cancer
research network, analysed the impact of the Directive. It reported that only 7 new clinical trials had been initiated in
Europe in 2005 versus 19 in 2004, and that a third fewer patients were enrolled.3 As further details emerged from their analysis, the negative impact of the Clinical Trials Directive was clear; for example,
EORTC found that trial costs increased by 85% and trial initiation was 5 months slower in 2005 than the previous year. Paperwork
and the increased workload for ethics committees were cited as contributory factors to this result.3
EORTC concluded that, despite the noble intentions of the Clinical Trials Directive, patients had lost out because access
to new treatments was being hindered by the new system. Another criticism was that the Clinical Trials Directive and associated
rules for EUwide clinical research was under the control of the Enterprise and Industry Directorate General, rather than the
EU bodies responsible for healthcare.3 Those involved in translational research therefore began to lobby for change because of fears that the Clinical Trials Directive
would cripple independent research into novel cancer treatments.
Admitting problems
Pressure from companies in the biopharmaceutical sector and from academic researchers appeared to eventually achieve a result.
In 2007, the European Commission (EC) and European Medicines Agency held a dedicated conference to examine the status of clinical
development in Europe and on the evaluation of the Clinical Trials Directive in practice in member states. A wide range of
stakeholders, from patient organisations through to companies, were invited to give their views. The event was considered
a success in that it initiated a dialogue between the different parties involved in European clinical research. Furthermore,
certain areas were identified for improvement, with different levels of priority, and progress on these fronts was to be assessed
at future timepoints.4
According to the official report, conference participants acknowledged that the Clinical Trials Directive had led to some
improvements. It cited a common legal framework, a legal basis for compliance with good clinical practice (GCP) and improved
protection for patients as positive points raised by the participants.4 Nevertheless, the report revealed the numerous problems that stakeholders had encountered relating to the efficiency of
the system and the burden of additional paperwork. In some cases, these problems were linked to different interpretations
and different implementation in the national legislation of the member states.
Given the scope of the Clinical Trials Directive and the numerous opinions raised at the conference, the discussion centred
on the nature of the contentious issues and how to address them. For some of the issues discussed, participants felt that
some were possible to resolve within the existing legal framework and overall it was felt that work should begin immediately
to resolve these issues to quickly achieve results. The main areas identified for priority were multinational clinical trials,
safety reporting and monitoring, non-commercial sponsorships/trials, Clinical Trial Application (CTA) dossier and process,
and investigational medicinal product (IMP)-related issues.4 In contrast, other issues (including increased transparency and availability of information on clinical trials, and the
application of ethical principles and GCP standards in developing countries) were almost certain to require changes to legislation,
and so more time and effort would be needed to address them.4
At the conference it was reported that most of the trials carried out by sponsors had been conducted at multiple sites and
multiple countries. In this context, participants detailed some of the EU-wide improvements as a result of the Clinical Trials
Directive, which included the unique identifier for a clinical trial in the EU (EudraCT number) and the common clinical trial
application form accepted in most member states.4 However, the participants revealed their frustration that there appeared to be little pan-EU agreement for consistency across
member states when it came to amendments for clinical trial submissions.4 For non-commercial sponsors, namely academic institutions, the Clinical Trials Directive put them at a distinct disadvantage
when conducting multinational, collaborative clinical trials, because of confusion over the requirement for a 'single sponsor'
for a trial. A suggested improvement was that multiple sponsorship of both multinational and national trials be allowed, so
that roles and responsibilities in different European countries could be shared on a contractual basis between the institutions
involved.4
