The Impact on Clinical Research of European Legislation (ICREL) project is funded by the European Commission’s Seventh Framework Programme (FP7) to measure and analyze the direct and indirect impact of the European Union Clinical Trial Directive 2001/20/EC and EU-related legislation on all categories of clinical research. The one-year ICREL project is being carried out by a consortium composed of the European Forum for Good Practice (EFGCP), European Clinical Research Infrastructure Network (ECRIN), European Organisation for Research and Treatment of Cancer (EORTC), Hospital Clinic I Provincial de Barcelona and the Ethics Committee of the University of Vienna.

Anecdotal evidence has accumulated ever since the EU CT Directive came into force in 2004 that participation in clinical research conduct for certain stakeholders, such as ethics committees, academics and small and medium-size enterprises (SMEs) has become more difficult, if not impossible. (SMEs are those enterprises that have fewer than 250 employees and an annual turnover less than 50 million euro.)

But, there have also been fears that large biopharmaceutical companies find it more cumbersome to conduct clinical research throughout the EU due to a lack of the true harmonization that the Directive was created to provide and that the number of clinical trials they conduct in the EU has decreased.

However, few hard data presenting the pan-European situation exist that demonstrate the Directive’s impacts.

The ICREL project was based on a joint conference organized by the European Commission and the European Medicines Agency (EMEA) called “Operation of the Clinical Trials Directive and Perspectives for the Future," held on Oct. 3, 2007, in London, in response to growing anecdotal evidence about the Directive’s adverse impacts.

The conference content comprised 25 oral presentations, 40 written submissions and six spontaneous submissions from various stakeholders in the clinical research industry. All described impacts of the Directive on a particular area of clinical research.

“The need was identified to collect information in a systematic, objective way all over Europe and on all stakeholders before and after the implementation of the Directive to find out what the impact of the Directive really was,” said Dr. Ingrid Klingmann, coordinator of ICREL and founder of Belgium-based Pharmaplex, a drug development and site support services organization.

It was clear after the conference that the two directorates of the European Commission with the most intimate knowledge of the Directive’s impact on an anecdotal level—the Directorate General for Research and the Directorate General for Enterprise and Industry—were interested in getting hard data about the Directive’s impact to inform changes they plan to make to the legislation early next year.

The ICREL project proposal received approval and funding from the European Commission on the first of the year. What may have contributed to the proposal’s success in getting approved was the fact that the EFGCP’s Ethics Working Party, which Klingmann co-chaired, had previous experience in writing a comprehensive report on ethics committee variability across the EU post-Directive. “The EFGCP Report for the Ethical Review of Protocols for Clinical Research Projects in the European Union” brings together comprehensive and consistent data gathered through structured interviews. That report was compiled with no budget from the European Commission. [See the April 2007 issue of The CenterWatch Monthly]

After receiving European Commission approval, the ICREL project got underway in February and is still gathering data on the Directive’s impact on the four stakeholder groups that participate in clinical research conduct in Europe: commercial and non-commercial (academic) sponsors, ethics committees and each EU member states’ regulatory agency.

The ICREL project is designed to provide metrics on the impacts of the Directive, either direct impact on clinical trials on medicinal products, or indirect impact on other categories of clinical research by analyzing completed questionnaires from the four stakeholder groups. ICREL needs at least 150 completed questionnaires from each group to be able to provide meaningful metrics. Each stakeholder’s questionnaire is unique in addressing the activities of that particular group.

“These four questionnaires are very different, but with those four questionnaires we are able to answer 95% of the questions that we have in the proposal. We sent the questionnaire to all national competent authorities of all EU countries and then we did a representative sampling of the other stakeholders,” said Klingmann. Data collected through the questionnaires will represent 90% of the information that ICREL will use to make objective analyses of the Directive’s impact and prepare recommendations for areas of improvement.

The other 10% of the project entails collecting open-ended comments and suggestions gathered from the questionnaires as well as a compilation of information from publications, earlier surveys and existing databases on the impact of the Directive. What ICREL and the European Commission want is a 360-degree view of the situation including figures, extant information and current thinking to inform the changes that need to be made. Key areas of interest are: impact on the quantity and complexity of different types of clinical trials; costs; timelines; workload for study authorization and execution.

“I think the most important thing really is that we get an understanding of: Is there a decrease of clinical trials? Is there an increase of resources, costs required? Is there any change in the timelines? What is the level of complexity? What impact did it have on your organization? Did you need to change a lot in order to be able to accommodate the new requirements? We need answers to those types of questions to really see where the problems lie and then of course also ultimately, Is patient safety improved now with everything we do or is it more bureaucracy than anything else?” said Klingmann.

The data collection is still ongoing.

Organizations interested in providing information should complete the respective questionnaire at www.eortc.be/ICREL.  The closing date for completing ICREL’s questionnaires is July 20. After that point the analysis of the data begins. In addition to finding out what the direct and indirect impacts of the Directive are on the four stakeholder groups, the European Commission also wants questionnaire respondents to share best practices and make recommendations on how to conduct clinical trials better in Europe. The last section of each questionnaire has space for stakeholders to provide this information.

ICREL has its work cut out for it not only in terms of the person hours it will take to compile and analyze what will be a high volume of data but also because legislation governing clinical research across the European Union has always been dogged by controversy and compromise.

“Creating clinical trials legislation was a very lengthy process because the first attempt to have clinical trials legislation was in the early 1990s. And because the stakeholders could not agree, it was shelved and brought up again at the end of the 1990s. At that time, the European Commission wanted to have a regulation, but neither industry nor the national competent authorities agreed with this. Also, the ethics committees wanted to have as much safety information as rapidly and completely as possible. What we got was a compromise on the lowest common denominator amongst all the interests of all the different stakeholders in the different European countries. I remember very well in 2001 when the Directive was released, there were a lot of complaints," said Klingmann. “In fact, the principles are good. A lot of things make sense in the Directive. The problem is that it is a directive. If it were a regulation, then we would not have this need for interpretation and harmonization. It is the national interpretation and practices by the different countries that makes it so complex.”

As part of its proposal, ICREL committed to holding a conference on December 2 in Brussels to share and discuss its findings—the hard figures and the comments and suggestions from stakeholders who completed the questionnaires. The conclusions from that meeting will be presented in the final report to the European Commission together with recommendations for changes in the legislative environment. All stakeholders are welcome to attend and participate in the conference.

The European Commission is clearly motivated to make changes to the Directive and eager to get the hard data and stakeholder recommendations to make informed decisions regarding those changes. With ICREL’s input, next year could bring swift action with changes for the better.