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A newly completed study of European ethics committees finds that the bureaucracy of each country determines the way the ethics committees operate.
There are still major differences in the way ethics committees across Europe deal with assessment of clinical trial protocolsvariations related to the country, and even to where they are located within individual countries. This is the principal conclusion of a newly completed study conducted by a Spanish researcher into how far harmonization has reached into the diversity of clinical trials regulation in the European Union.
The studya PhD thesis at Valencia University by Javier Revuelta, who works in Spain for Merck & Cosets out where the attempts to offer a level European playing field for clinical trials have worked, and where they have not. Revuelta has provided his findings exclusively to ACTs View from Brussels, and told this columnist why he started the study, and what he concludes from it.
His thesis examines in some detail compliance in Europe with the good clinical practice (GCP) norms from the International Conference on Harmonisation (ICH). His work is based principally on data from 1999, obtained from nearly half the ethics committees in Denmark, Germany, and Spain.
Among his key findings are that differences in the conduct of ethics committees correspond closely to the different approaches taken by officialdom across the countries that make up the EU. It is the bureaucracy of each country which influences the manner in which ethics committees operate, he says.
Fifty-eight percent of the ethics committees in the sample studied in Germany, Denmark, and Spain were working in 1999 without having fully adjusted to the operating procedures in the ICH recommendations for GCP, he reports. The great diversity of perimeters defining European ethics committees confirms that they have not achieved the level of harmonization required to evaluate trials conducted at an international level. The start-up of trials in Europe is frequently held up unnecessarily by excessive bureaucratic delay in the ethics committees evaluation.
More to the point, he predicts, there will be real problems in ensuring that ethics committees will be able to adapt to the EU rules to evaluate trial protocols in the time required and according to the new rules, and to follow them up. National and local influences need to change. Germany showed no improvement in common approach in the study that Revuelta conductedvariations and divergences predominated. In Denmark, the data revealed likely problems in providing for evaluation of trial centers and follow-up. Spanish committees are too slowand there are too many of them.
Some of the detailed findings show wide disparities. Committees in Spain urged the sponsors to provide further information on the results on 39 occasionsagainst six times in Germany. Similarly, Spanish committees urged the inclusion of more information on the development of the study on seven occasionswhile no German committee did.
The findings also reveal wide differences in the way that committees behave if they are regional or linked to the trial center, if they are hospital-based or linked to small clinics, university-based or linked to groups of doctors, and so on.
From his own point of view as a clinical trials professional, Revuelta says that what struck him most forcefully in his own research is the general absence of professionalism in document management revealed among almost all ethics committees. This compromises their ability to ensure the protection of subjects enrolled in trials and the scientific validity of the findings, he claims.
Revuelta also remarks on what he terms the excessive review of the scientific aspects of protocols. Many ethics committees are focusing on this, which implies repetition of work already being done by other committees and by the regulatory authorities, he chargesadding that this generates delays in getting a decision. At the same time, ethics committees dont look closely enough at the local aspects of the protocol. They dont check the suitability of particular studies in relation to the trial centers they are going to be conducted in. Study design is fundamental, but an ethics committee should verify the suitability of the study in the conditions in which it is going to be carried out, he says. Ethics committees were also slack in following up incidents during trials, in assessing the way trials are conducted by investigators, and in checking on the results.
In his opinion, it has taken a long time for local ethics committees to take on board the idea of European harmonizationlargely because they are made up of local people. Representatives of each country, with its own culture, language, religion, investigational methods, health system . . . werein some casesjust starting to hear in 1998 about international recommendations that had come into force a year earlier. And they are still subject to national or local legislation, with its own administrative and bureaucratic characteristics, while they are evaluating the ethics and the suitability of a protocol which is also being evaluated by another ethics committee thousands of kilometers away.
His study also looks ahead to what the prospects are for improved and more harmonized performance after full implementation of the EU directive on clinical trials (2001/20/EC). This sets out conditions and timing for member states to establish a system for coordinating the work of ethics committees in terms of making them more agilewhich is currently a major challenge, he insists.
Given that the ICH recommendations still have no legal force, the average level of ethics committee compliance with them is just about satisfactorybut there are key areas where implementing the EU directive are likely to prove difficult, he says.
He highlights as particularly important the evaluation of the suitability of trial sitesin terms of the physical conditions, and the quality of the investigating team, their availability, their resources, and their experience, particularly in relation to the local incidence of the pathology under study. He also focuses on setting up an adequate system for monitoring and control of trials after they have started. And he sees big difficulties in ensuring that the new EU rules will be implemented in a way that will bring about protocol evaluations that are both well-judged and rapid.
A European adventure?
After having worked for some time in areas that were linked to European Union affairs, he was already conscious of what he terms the European adventurethe development of harmonized approaches, and the implementation of rules that apply right across Europe. Then, when he started to work in clinical trials, and saw how complicated the authorization process was, he became fascinated by the role of clinical investigation ethics committees. What struck him particularly was that they are referred to in all the international recommendations, and everyone who works in clinical trials, anywhere in the world, talks about them as if they are the same everywherein the face of the evidence that, clearly, they are not.
It seemed odd to me that in a country as small as Belgium there should be more ethics committees than in France and Germany put together. Above all it wasand isvery strange that the same protocol can be rejected or approved according to which committee does the evaluation. Even more to the point, the reasons for rejection are so often completely different among committees that have turned down a study (without even mentioning the time they take).
So Revuelta started asking himself: Are ethics committees the same in different countries? How do they differ? Do they have the same duties? Logic, and my own knowledge of various countries, suggested to me that there had to be significant differences, he told View from Brussels.
His starting point was that in its clinical investigation, when a multinational company is working in different countries to conduct trials, it agrees on international norms or recommendations, a protocol, standardized internal working procedures, and a single working languageinvariably English. But then there are a series of national particularities that make it obvious that harmonization is still something for the future, and that at present (and even more in 1998, when I started my study) it simply does not exist.
This was what led him to decide that ethics committees would be an excellent index to measure the extent to which good clinical practice harmonization had been achieved across countries.These committees were like a thermometer of the temperature of harmonization in each country and each region, he says, because they are the point at which all the aspects converge, making them into individual observatories of how far common methods exist.
What he was looking for was specific data from different countries to check his own concerns about how closely the impending EU rules would be met over the coming years. He suspected that when the objectives and timetable for harmonization were being setthere were failings or a lack of planning among the authorities at international, European, and national levels. Have they been realistic in what they were setting out to do? he wondered.
His conclusion is, pretty clearly, that they have not.
At the heart of the problem is the question of quis custodiet. There are no systems in place for monitoring the functioning of ethics committees. Who guarantees that they are operating correctly? he asks. And he lists his own remedies. EU member states should set up national systems, to ensure effective protection of the population, correct scientific review, and administrative flexibility that would assist the development of clinical investigation in the countries of Europe, he urges.
In addition, each member state should establish a national network of what he calls reference ethics committees. There should be fewer than 10 per country (often as few as 5) with, if necessary, a system of rotation. They would be responsible for the scientific and ethical assessment of studies, and for supervising the information coming from local committees. The local committees would be responsible for checking the suitability of trial sites before studies start, and for follow-up during the course of trials, and they would pass their information up to the reference committees.
National health authorities would be responsible for coordinating the establishment and accreditation of the committees, and for ensuring effective communication between them. But the European Union should set up a simple mechanism for inspections and hearings to assess the ethics committees themselves, to ensure their compliance with clear guidelines for them to follow. This, he says, would be something that could really contribute to an approximation and harmonization of clinical trials at the European level.
As a footnote, it is worth reporting that Revuelta says he received a good level of cooperation from ethics committees in conducting his research. He also says some complimentary things about Applied Clinical Trials, which has been reporting on the evolution of clinical trials regulation in Europe for many years, and in this column since the early 1990s, but that unfortunately there was no contact with or participation from the European Commission. I tried to get in touch several times, he said, but there was no interest.