Squeezing the European Union Into Shape

The unfailing fascination of writing about European affairs is that every time Europe seems to have found any solution, another twist emerges to present a new challenge. And in clinical trials—just as much as in resuscitating the Balkans, or regulating state aid to failing companies, or creating a single currency, or upgrading transport infrastructure—the harder Europe tries to squeeze itself into shape, the more it highlights its divergences.

In fact the clinical trials domain is offering rich pickings these days for students of diversity. As the May 2004 deadline approaches for full implementation of the European Union clinical trials directive, with all its guidance finally in place, the clearer it is that Europe’s bid for harmonization is less than complete. The clinical trials community in Europe is increasingly apprehensive about the prospects, despite the protracted discussions about how to implement the new EU rules that were initially supposed to resolve national differences.

The European Union is passing through a “critical phase of building a robust regulatory framework for clinical trials,” according to Dr. Roger Bickerstaffe, chairman of the European Forum for Good Clinical Practice, which organized a meeting on the subject in Brussels on October 6-7. And he warned that it is essential to establish some clearer definitions if the regulatory framework is to function correctly.

Who is the sponsor?

One of the problems the meeting focused on was the imprecision over the responsibilities of the trial sponsor. “For European patients and healthy volunteers participating in clinical trials, as well as in the interest of future patients, it is of critical importance that this role and the accompanying responsibilities are well defined and fully supported,” according to Dr. Bickerstaffe. But although the new EU rules will reinforce the role and responsibilities of the sponsor, they have not defined precisely who the sponsor is: “The structure and make-up of such an organization remains open and has recently been identified as problematic,” he says.

The new requirement for a single clinical trial sponsor “threatens the future of publicly funded clinical research,” according to Janet Darbyshire of the United Kingdom’s Medical Research Council. As she pointed out, the new requirement may suit the needs of a pharmaceutical company bringing new drugs to market, “but fits uneasily with the partnership arrangements for publicly funded trials.” A large company such as GlaxoSmithKline or Bristol-Myers-Squibb has the resources and all-round expertise to take on all the responsibilities of the sponsor. But, Darbyshire insisted, a lot of vital clinical research is conducted by smaller firms, or public research organizations, or hospitals—often in consortiums where different responsibilities of the sponsor are shared.

Jacques Demotes of the French Institut National de la Santé et de la Recherche Médicale told the meeting: “Sponsorship of Europe-wide multi-centre trials is becoming increasingly challenging for smaller biotechnology firms and academic institutions, universities or hospitals.” It is hard for a public hospital in one country to effectively supervise the precise conduct of a trial which is conducted in part in one or more other countries. And “the current fragmentation of clinical research infrastructures, both at the national and European levels,” aggravates the problem, he said. The same challenge confronts other organizations involved in clinical trials, from nongovernmental organizations and charities to investigator- or researcher-initiated trials.

Ethics committees at odds

The ill-defined role of ethics committees is also preoccupying the clinical trials sector. Again, the new EU rules were initially intended to clarify this function, but in the event have fallen far short of harmonization—so member states may choose to implement the new rules in very different ways. As Terry Stacey of the Central Office for Research Ethics Committees in the United Kingdom said: “Ethical values differ amongst various EU populations, and there are variations in the remit of ethics committees, with some carrying out a regulatory function in addition to providing an ethical opinion. Some committees have a major role in scientific review; others rely on the previous opinion of experts. Some interpret the law; others leave this to a wider research governance framework. And the composition of committees varies accordingly.” He warned that unless a “European dimension” is created for the wider frameworks within which these committees work, there is unlikely to be much further convergence across Europe.

Monika Siebert Grafe of the University Hospital in Heidelberg spelt out some of the challenges that multinational trials face when presenting an ethical justification for ethics committees. She listed the variety of cultures, histories and traditions across Europe, the lack of harmonization of medical and scientific standards from country to country, and the differences in organization and constitution of ethics committees. Even where an ethics committee is itself independent, the organization it belongs to may influence its opinion, she suggested.

Worse, as Dr. Ingrid Klingmann of the Pharmaplex consultancy lamented, those responsible for clinical trials review in the EU’s member states do not talk to one another about how they handle the matter. “It’s as if they are resigned to divergence,” she told ACT, citing key figures who have remarked “It’s not my job to worry about harmonization. My job is national.”

The complication of EU enlargement

And on the same day next year that the new rules come into force, ten new member states will join the EU: Poland, the Czech Republic, Hungary, Slovakia, Estonia, Latvia, Lithuania, Slovenia, Cyprus and Malta—with even more differences coming into the picture. Professor Tamas Paal of the Hungarian National Institute of Pharmacy remarked that the enlarged EU will contain ethical and regulatory approval systems of clinical trials with divergent traditions, and since the new rules provide “only a framework,” the result is that “the clinical trial review system will vary considerably between present and new member states.”

According to Professor Roman Lorenc of the Children’s Memorial Health Institute in Warsaw, the main discordances between Polish and EU practice on ethics committee operations include the absence of a single national decision-making body, and different application formats, insurance requirements, and timelines for decisions.

And Professor Jozef Glasa of the Slovak Health University in Bratislava pointed out what he saw as the key current gaps between EU member states and the countries of central and eastern Europe in terms of ethics review. There is missing legislation, he said, and even when the legislation is in place it does not always work. There are diverse views on what sort of information committees should receive and how they should be constituted. There is often insufficient competence of members—they have too little time to do the job, or funding is not available, there is too little prestige attached to the job to provide the necessary motivation, or members have their own hidden agendas. Inconsistent or conflicting opinions often emerge, waiting times are long, and there are often no standard operating procedures in place.

Ethics in research

The matter is further complicated by parallel EU rules on what sort of research and development it will help fund. As Fergal Donnelly of the European Commission told the meeting, there is EU money available for ethical issues such as research with human beings (including Phase 1 and 2 clinical trials in adults and children), use of embryonic stem cells, use of biological material of human origin, and research with animals. But there are conditions. All applications for funding have to contain a discussion of the potential ethical aspects of the proposed research and its objectives, its methodology and the possible implications of the results. This has to justify the research design, explain how ethical requirements will be fulfilled, and indicate the relevant national regulations in the country the research will take place. And there are some tight exclusions on precisely what can be funded in these fields—mainly out of deference to differing national sensitivities across the EU member states. Research activity aiming at human cloning for reproductive purposes is absolutely out. So too is research intended to modify the genetic heritage of human beings in a way that would make such changes heritable—but researching relating to cancer treatment of the gonads can be financed. And, at present, anyway, there is no possibility of winning EU funding for research intended to create human embryos solely for the purpose of research or for the purpose of stem cell procurement, including by means of somatic cell nuclear transfer.

No obligation to harmonize

The EU rules “do not impose an obligation on member states to harmonize or unify their understanding of the ethical principles applying in the field of research with human beings,” remarked Professor Dominique Sprumont of the University of Neuchâtel in Switzerland. And “even if the member states all share the principle that some basic ethical rules should apply to research with human subjects, they do not share the same understanding in the way to apply them.” She also pointed out that according to her assessment, 14 of the 15 EU member states have still not completed the formal implementation of the clinical trials directive.

Faced with this series of challenges—continued fragmentation of the EU regulatory framework for clinical trials, only skeletal EU rules that leave much of the choice still up to member states as to how they control trials, and late implementation of the rules that have been agreed—EFCGP has tried to come up with a pragmatic solution. It has establishing a “European Partnership for Implementing the Clinical Trials Directive” with medical research organizations and other interested groups across Europe, in the hope of achieving at least some consensus on clinical trials governance. This is currently preparing a position paper defining the roles and responsibilities of sponsors and funders of clinical trials. “We are looking for a European dimension,” said Francis Crawley, EFGCP’s ethics officer. “We are encouraging ethics committee members to get to know one another across national boundaries, so they can learn to share practices. EU directives will not achieve harmonization. We are aiming at creating an education curriculum for ethics committee members, to help them network and to bring them together.”

But, as the discussions at the meeting demonstrated clearly, the risk grows rather than diminishes of divergent interpretation from country to country.

Out of Africa

Following this column’s recent coverage of the European and Developing Countries Clinical Trials Programme, a footnote is appropriate on the outcome of the visit to southern Africa by European Research Commissioner Philippe Busquin.

Addressing a World Health Organization conference in Johannes-burg during his September trip there, he called on health ministers from 46 African states to facilitate the training of doctors and pharmacists and to make ongoing assistance available in order to establish a research capacity and stem the exodus of skills. “The EDCTP needs the support of African governments and communities if it is to work,” he insisted.

The Commissioner’s reception was not universally welcoming. Manto Tshabalala-Msimang, South Africa’s Minister for Health, who chaired the meeting, even attempted to postpone the Commissioner’s speech until the following day. Following this snub, WHO Regional Director for Africa, Dr. Ebrahim Samba, said he had never heard of the clinical trials programme and needed more information. Even the new Director-General of the WHO, Dr. Jong-wook Lee, said afterwards: “We need to know more about the EDCTP. It sounds like a good idea, but we should work on our communication.”

But Dr. Pascoal Mocumbi, prime minister of Mozambique, was more positive about the EDCTP. “Our problem in Africa is that donors give money for short-term projects. When the money runs out the projects stop and we are back to where we started. The EDCTP could be a way to create sustainable, long-term solutions to some of our needs.”