Change is in the air for the European Clinical Trials Directive - Pharmaceutical Technology

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Change is in the air for the European Clinical Trials Directive
Though many advantages are associated with the European Clinical Trials Directive, complexities have emerged since its introduction in 2004. Since 2007, efforts have been made to raise the issues and address the negative impact of the Directive, and the European Commission is currently assessing stakeholder feedback from a public consultation document, which could lead to changes for the European Clinical Trials Directive.


Pharmaceutical Technology Europe
Volume 22, Issue 5


Faiz Kermani
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


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