Multinational trials have become increasingly complex and timelines have lengthened since the European Union Clinical Trial Directive 2001/20/EC went into effect. This has resulted in stakeholders' need for more staff and ultimately higher costs to run drug development programs in Europe. While stakeholders have anecdotally drawn similar conclusions, a report by The Impact on Clinical Research of European Legislation (ICREL), is now able to provide hard data to back up these claims. The report demonstrates the significant impact of the directive on all stakeholders.
ICREL collected more than 220 completed questionnaires from three of the four stakeholder groups it surveyed--commercial sponsors, non-commercial sponsors, ethics committees--as well as completed questionnaires from 23 of the 25 EU member state competent authorities and two non-EU competent authorities from countries integrated within the EU regulatory system. Data collected through these questionnaires, mainly comparing 2003 and 2007, made up 90% of the information that ICREL used to make objective analyses of the Directive's impact and prepare recommendations for areas of improvement. The remaining 10% came from 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.
The one-year ICREL project was carried out during all of 2008 by a consortium composed of the European Forum for Good Clinical Practice (EFGCP), European Clinical Research Infrastructure Network (ECRIN), European Organisation for Research and Treatment of Cancer (EORTC), Hospital Clinical I Provincial de Barcelona and the Ethics Committee of the University of Vienna. Findings were discussed at a December ICREL conference in Brussels, after which the report was written up.
"There are some very interesting findings," said Dr. Ingrid Klingmann, coordinator of ICREL and founder of Belgium-based Pharmaplex, a drug development and site support services organization. "In principle, everybody agrees that we have made a good step toward harmonization. The problem is that this is a directive. This allows the national legislations to implement the principles but not the text word for word. Every country had legislation for clinical trials before the directive came into force, and they tried to fit the principles into the existing system. In this way, the differences between the countries have become even larger, rather than smaller."
Among the report's more salient findings are that between 2003 and 2007:
The increase of full-time equivalents (FTEs) for the different tasks of the various stakeholders increased between 30% and 100%.
For multinational trials, on average, the time from finalizing the protocol to first patient in has increased from 115 days to 152 days, or 30%.
The number of sites and countries participating in multinational clinical trials have increased, but the number of patients participating has stayed the same.
The mean timelines for clinical trial application (CTA) review by the individual competent authorities has decreased from 60 to 49 days.
25% fewer clinical trial applications were submitted from non-commercial sponsors, though some countries had strong or even dramatic decreases and others experienced an increase.
The annual budget of ethics committees increased by 50% due to the significant increase in the number of substantial amendments and suspected unexpected serious adverse reactions (SUSARs) to review.
Non-Commercial Research Suffers
One of the original intentions of the directive was to avoid having two standards between commercial, or industry-sponsored trials, and non-commercial, or investigator-initiated academic trials, Klingmann said. Requirements for both kinds of trials under the directive are the same, which the ICREL report reveals has resulted in fewer trials being conducted in the academic setting. This is mainly due to the administrative burden associated with fulfilling the directive's requirements and the lack of sufficient funds, resources and capacity.
While most industry-sponsored clinical research is ultimately conducted for marketing authorization purposes, academic research tends to study treatment optimization with approved drugs. Nevertheless, these approved drugs are considered investigational medicinal products under the directive and fall under the same requirements as for non-approved drugs, which Klingmann finds is often unnecessary.
"Everybody agrees that the quality of scientific approach, data generation and patient protection needs to be the same, but the amount of documentation required, level of monitoring, reimbursement conditions for study medication, etc., should be handled differently in studies with approved drugs, for treatment optimization purposes or in an observational setting, often performed in the academic environment," Klingmann said.
ICREL is working toward compiling criteria agreed upon by both commercial and noncommercial sponsors that would form the basis for a risk-based approach to research. ICREL is building on the work of ECRIN and the European Science Foundation to come to an agreed-upon definition of the term "risk."
"The next step is to find out how far this risk-based approach can be applied--for what types of studies, for what types of products, etc. That is a process that is ongoing at the moment," Klingmann said.
ICREL's final report reveals discrepancies not simply between different stakeholders but also between EU member states, which have defined the scope of the EU Clinical Trials Directive very differently in their respective national legislations. At two opposite ends of the spectrum are Germany and France. Under Germany's strict definition, clinical trials refer only to those trials that study drugs. In France, the definition covers all types of clinical research, including trials involving surgery, radiotherapy and others.
Difficulties with these two definitions arise when clinical research with multiple study arms is conducted in both Germany and France. For example, an oncology clinical trial comparing two surgery techniques with radiotherapy and a drug treatment would fall under the clinical trial directive in both Germany--because there is an arm studying a drug treatment--and France. But if there were no drug arm to the study, it would not be considered in Germany to be a clinical trial falling under the German Drug Law, but it would be considered a clinical trial and thus fall under the drug law in France. This situation creates confusion not in small part because clinical research personnel are not always aware of this fact or have difficulties adjusting the trial dossier submission process to the different national requirements.
The scope of the directive is also not consistent From country to country with regard to observational, non-interventional trials. In some countries, such as Germany, these types of trials do not fall under the scope of the directive, but in others, such as France, they do.
"A lot of non-commercial sponsors are uncertain when they are in this late stage of drug development whether this type of trial falls under the directive or not. For example, there was a report from one very large pediatric oncology trial for which the children were randomized to Treatment A or Treatment B, and then it was open treatment. Both were established treatments. They just wanted to compare them and find out which was better, but they wanted to do this objectively and randomize the children. Then it was normal treatment, simply observed. The researchers thought this was not a clinical trial, but even Germany decided that it was, according to the directive, because randomization is a clinical trial activity," Klingmann said. "It's really tricky. We have a lot of definitions not clarified. We have not clarified what a substantial amendment is. We have not sufficiently clarified what an investigational medicinal product is or what an observational trial is and is not. This is not clear in Europe."
ICREL is now in the process of trying to improve the current situation by clarifying such definitions. This process began this past December with the ICREL Conference, attended by 300 people representing all stakeholders. ICREL wants to avoid the pitfalls of the last go-round.
Speaking With One Voice
"The problem when we discussed the directive before it came into force was that the different stakeholders--commercial sponsors, ethics committees, and the competent authorities--discussed amongst themselves their needs and they came with their requests to the [European] Commission. The Commission was in a very difficult situation at the time because they had to find the compromises among all the different stakeholder requests," Klingmann said. Non-commercial sponsors, unfortunately, did not make their wishes clearly known to the Commission until after the directive was in effect, she said.
An underlying problem in the EU is the tension between centralization and decentralization of legislation. The European Commission (EC) and EU member states are often working at cross purposes, with the EC trying to propose European legislation and the member states trying to minimize its impact. While this tension will always undergird any proposed European legislation, the ICREL Consortium wants to make sure that stakeholders speak with one voice to the EC when they submit proposals for change this time around.
"This time, we should bring the stakeholders together early, let them work out where there are common needs, where there is common ground, where there are really big differences, where to work on the differences and then find a way to bring the differences among the groups together, have them work out the best solutions that fit best for all of them and then come up with a combined proposal to the Commission, so the Commission then only has to deal with the member state issue. That is what we are doing now," Klingmann said.
To this end, ICREL has also become part of a larger initiative, Roadmap Initiative for Clinical Research in Europe, involving nine organizations--ECRIN, ICREL, European Group for Blood Marrow Transplantation (EBMT), Centre for Blood Marrow Transplantation Research (CIBMTR),EFGCP,EORTC,CLINT: Facilitating international perspective clinical trials in stem cell transplantation, University of Central Lancashire-Centre for Professional Ethics (UCLAN), European LeukaemiaNet (ELN)--to start this common opinion generating process.
At the top of the Initiative's agenda is finding a system, covering all types of trials, where the European Medicines Agency and the national competent authorities work more closely together in the CTA process to avoid duplication of effort. As it stands now under the directive, sponsors must seek review from every competent authority in every country where they run multinational clinical trials. After the competent authorities do the same review, many conclude different things and come back to the sponsor company with additional requests, which can result in substantial amendments to reconcile the various requests. This adds time and money to the process.
EFGCP is organizing the first of a series of workshops, starting on July 7, called "A Single European CTA: Dream or Option." Other upcoming workshops will include discussions about a risk-based approach, safety reporting requirements, sponsor responsibilities and definitions of co-sponsorship, definitions of terms in the directive and ethical review. The final workshop will discuss all the results from the previous ones and culminate with a list of suggestions for improvement to the EC.
Ultimately, the Road Map Initiative for Clinical Research in Europe would like new, robust legislation, but the European Commission is currently under a major reorganization after European Parliament elections last month. Therefore, the Commission will make a decision next year about whether it is necessary to go through the lengthy and difficult process of developing new legislation. In the mean time, the Initiative is looking to make as many productive proposals for changes to the current directive as possible.
"What we really hope is that this will be a first step and that there will be a snowball effect and that we will be able to bring more organizations into this initiative so that we have a broad, common basis of stakeholders," Klingmann said. "The more people talk with each other and the more they understand the needs of the others, the less energy is wasted on emotional debates at a later stage when there is a proposal on the table, because people know then that this is a compromise and accept that more easily when they have been involved in the discussion and when they know that their representatives have been involved in the compromise."