Change is in the air for the European Clinical Trials Directive

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

Faiz Kermani

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

Encouraging further improvement

Since 2007, there have been further efforts to address the negative impact of the Clinical Trials Directive. In 2008, the EC launched a study entitled Impact on Clinical Research of European Legislation (ICREL). ICREL was a longitudinal, retrospective, observational and comparative study to assess the impact of the Clinical Trial Directive, for the period 2004 to 2007, by examining the number, size and nature of clinical trials, and assessing workload, resourcing, costs and performance.^4,5 ICREL concluded that overall there had been no reduction in clinical trial activity in the EU. However, it did show that conducting clinical trials in the EU had become more costly and burdensome, thereby validating concerns raised by participants at the 2007 EC-EMEA conference.

ICREL found that, while harmonisation focused on quality standards for clinical trials in different member states, there appeared to have been no effort to standardise ethics committee systems and approval procedures in the different countries.⁵ Safety data reporting was also handled differently by the different member states, causing additional administrative burden. For example, different member states have different interpretations of what constitutes a suspected unexpected serious adverse reaction (SUSAR) and this has caused an information overflow for the EU central database.⁶ There has been a sixfold increase in the number of safety data reports lodged since the Clinical Trials Directive took effect, as sponsors attempt to make sure they are complying with safety requirements.⁶

The benefit of ICREL was that it provided metrics for the issues that were considered to be damaging the European clinical research environment. The data should be useful when it comes to discussions about how to best revise European clinical trial legislation. At the end of 2009, the EC sent out a public consultation document and asked stakeholders whether the rules for European clinical trials should be changed.⁶ The deadline for comments was 8 January 2010.

It will be interesting to see how the EC follows up on feedback received and how it uses the ICREL data. For example, the ICREL results favoured a simplification of the Clinical Trial Authorisation (CTA) process through a single CTA for multinational trials by showing that it could reduce duplication of effort and also save time and cost.⁵ The authors of the ICREL report have suggested that the study be repeated at regular intervals to monitor the impact of EU legislation on the clinical trials environment. Furthermore, they suggest a comparison with the clinical trials environment in nonEU regions, such as the US, Canada and Japan.⁵ International analyses of this nature could also be valuable in ongoing efforts to make the EU more competitive for pharmaceutical R&D.

The author says...

• The European Clinical Trials Directive was introduced in 2004, but the complexities of developing a pan-European system to the satisfaction of multiple parties and member states led to delays in implementing the Directive in many countries.

• Companies operating in Europe as well as academic institutes found the new processes unclear.

• Pressure from disgruntled researchers and companies led to a meeting in 2007, held by the EC and European Medicines Agency, to examine the status of clinical development in Europe and the Clinical Trials Directive in practice.

• Since 2007, efforts have been made to address the negative impact of the Directive — the EC is currently reviewing feedback from a public consultation document, as well as data from its own research, to assess whether changes need to be made to the Directive.

Faiz Kermani is a freelance consultant and President of the Global Health Education Foundation, a charity that supports medical education and research projects in developing countries. He is a member of Pharmaceutical Technology Europe's Editorial Advisory Board. faiz@doctors.org.uk

References

1. F. Kermani and C. Narayan, Nature Biotech (February 2005).

2. Pharmaceutical-int International, "The EU Clinical Trials Directive — One Year On" (2005). www.pharmaceutical-int.com

3. A. Hemminki and P-L. Kellokumpu-Lehtinen, BMJ, 332, 501–502 (2006).

4. European Medicines Agency, "European Commission-European Medicines Agency Conference on the Operation of the Clinical Trials Directive (Directive 2001/20/EC) and Perspectives for the Future. Report on the European Commission–European Medicines Agency clinical trials conference" (2007). www.ema.europa.eu

5. European Commission, "Assessment of the functioning of the "Clinical Trials Directive" 2001/20/EC. Public consultation paper" (2009). http://ec.europa.eu

6. MedNous, "Should EU rules for clinical trials be revised?" (2009). www.mednous.com