Europe Looks at Trials in Future Research

European Parliament debates on the allocation of research funds reveals Euro-MPs views of clinical research in medicines development.

There has been plenty of discussion of clinical trials in Europe over the last few weeks. Not so much in terms of the European Unions new clinical trials directive, which is gradually edging itself toward implementation, but in terms of European research.

The forum for most of this discussion has been the European Parliament, which held two major debates on the subject during Novemberone on the European Unions plans for a $15 billion research support program for the next six years, the other on how the EU should face up to the challenges of genetics. After a lengthy and complex debate on the research program in mid-November, the parliament gave the backing that is needed for the program to go aheadalthough it called for some significant changes, which will have an impact on clinical trials. And at the end of November, a heated debate on genetics produced some spectacular confrontations between the pro-science and anti-science lobbies, without arriving at any definitive conclusion, because the participants could not agree on a common view.

The nature of these debates is instructive about how Euro-MPs view research in general, and medical research in particular. Euro-MPs do not hold sole responsibility for European Union legislation (they are only one of the institutions involved in the creation of EU law through the Unions convoluted procedures), but their views are illustrative of many of the major currents of thought that underpin the evolution of EU rules. So this months column reviews some of the points made in the parliament about clinical trials, as a guide to how this institution sees the role of trials in medicines development.

Research funding
The debate on the multiannual EU framework program 20022006 for research, technological development, and demonstration activities ranged widelybecause the program covers aviation and materials science as well as health. But most of the discussion was on how the funding to be made available for health should be allocated. The original idea, proposed by the European Commission, was to focus the resources entirely on genomics and biotechnology, so as to help the search for fundamental techniques that could be applied across a range of diseases. But the parliament insisted on making specific provision for major diseases too, so the parliaments final resolution split the health funding roughly in two, with half for genomics and biotechnology, and half for key diseases, such as cancer and diabetes. And much of the emphasis was on ensuring that the European-level possibilities for clinical trials are taken advantage of fully. The parliament specifies:

In these medical fields, the objective . . . will be to develop improved patient-oriented strategies for the prevention and management of disease and for living and ageing healthily. The research will therefore concentrate on translating the new knowledge being created by genomics and other fields of basic research into applications that improve clinical practice and public health.

And, according to the final vote in the parliament,

For cancer, the priority theme will sponsor a patient-oriented European Initiative on Cancer Research, containing three interlinked components: establishing a European Centre for the Exploitation of Research on Cancer, preferably by developing existing structures and networks, with the purpose of developing evidence-based guidelines for good clinical practice and improved public health strategies by accelerating the translation of existing research results into applications; supporting clinical research, particularly public-interest clinical trials, aimed at validating new and improved interventions; and supporting translationary research aimed at pulling basic knowledge through to applications in clinical practice and public health.

The justification for this modification to the Commissions proposal was that it was necessary to specify the contribution that can be made to cancer research at the European level.

Tens of thousands of people die of cancer every year in the EU. Only if the Union succeeds in conducting more translational research, coordinated at EU level, will it be in a position to compete with the U.S. to keep top researchers in the EU. In addition, this will contribute to the development of medicines in this area in the EU. Improved coordination between the EU and the Member States will enable the overall budget for cancer research to be used more efficiently and will give a boost to the combating of cancer in the EU.

Another modification from the parliament insisted that provision should be made for

Research linked to cancer, cardiovascular diseases, diabetes and diabetes-related diseases, degenerative diseases of the nervous system (including Alzheimers Disease, Parkinsons Disease and experimental treatments now under investigation for new variant Creutzfeldt-Jakob Disease), psychiatric diseases, cardiovascular diseases, viral hepatitis C, allergies and metabolism diseases including diabetes and rare diseases.

It called for transnational research and comparative studies and coordinated development of European databases to provide comprehensive pictures of the diseases; cooperation with and support for existing networks; interdisciplinary networks, to be set up preferably by linking existing networks; clinical cancer research; exchange of clinical practice; and clinical trials on new drugs. The justification, the parliament said, was self-explanatory.

Some of the references to clinical trials that occurred in the draft report were not included in the final version that the parliament adopted at the end of its debatebut again they offer an insight into some of the thinking conditioning the clinical trials world at the European level. Less attention can be paid to some of these proposalsfor instance one on Research on medical use of cannabis, which took account of the emerging interest in the medicinal use of cannabis, not only in the Netherlands . . . other EU governments are showing interest. The ill-fated draft amendment added that

on several occasions the International Narcotics Control Bureau called on the associated countries to stimulate clinical trials with cannabis. Although there are indications that cannabis could be useful in certain diseases, its therapeutic use is not evidence based. Historically over 40 indications have been reported. The most promising are multiple sclerosis, appetite stimulant in AIDS-wasting syndrome and cancer, nausea and vomiting in cancer chemotherapy, epilepsy, several forms of pain, and glaucoma.

But EU backing for such trials will have to wait for another day, it seems.

However, another draft amendment shows a growing recognition among at least some Euro-MPs of the rigors of successfully conducting trials. It urged support for research which assists the battle against serious diseases, noting that priority should be assigned to research efforts which one member state alone cannot undertake or cannot undertake as efficiently as the European Union and which will directly benefit patients within the foreseeable future. The measures in this field would also support policy-orientated research, the report states. It continues, This would include, for example, research documenting trends in risk factors; research into the effectiveness of interventions to tackle inequalities in health; research into the reasons for survival differences in treatment outcomes; and health services research. The justification is that

in a whole range of areas, e.g. combating rare diseases and the field of childrens diseases, it is often not possible for one member state alone to carry out the necessary research. Particularly in the case of clinical trials, large numbers of patients are needed. These can more readily be found on a European scale than if research is confined to a single member state.

Genetics
The draft report on genetics noted a lack of coherence in EU rules governing research: There is a plethora of divergent, or at any rate not wholly consistent, national rules applying at every stage from development to the clinical trial, and that this is recognised to pose a severe limitation, making it difficult to develop and test new biomedicines on an EU-wide scale, although these are activities that should be encouraged.

The report goes on to recommend as a first step, the EU directive on clinical trials should be transposed into national law as soon as possible. An explanatory statement annexed to the draft report says that the clinical trials directive, which lays down provisions for implementing good clinical practicedefined as an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjectsconstitutes a first element of harmonised regulation of biomedical research and development.

But if the EU creates a framework in which the opportunities are exploited to the full, it said, EU citizens will be able to benefit from the significant health advantages of genetic research, and further investment will gravitate toward European science and the pharmaceutical industry, which are having to operate in an increasingly more competitive global context, it said.

At the heart of the debate on genetics was the tension between helping science move forward, on the one hand, and protecting human dignity on the other. What matters, said the draft report,

is to weigh up the risk against the opportunities being opened up by science and to refrain from delaying the advent of useful technologies. Responsibility toward future generations applies not only to the responsibility for doing things, but also to the responsibility for not doing things that theoretically and in practice could be done. The debate on human genetics and its applications is taking shape haphazardly and often does not start until after a product has become available. We must take up the challenge of drawing up essential ethical guidelines, the substance of which should be such as to serve as a basis for general assessment of the development and use of human genetics and cover rules seeking to safeguard considerations such as: free and informed consent, assessment of risks in relation to benefits, protection of the health of persons involved in clinical trials, scientific assessment of stem cells for therapeutic uses, the anonymity of donors, management of stem cell banks and their confidentiality, a ban in trade in embryos, and import and export of stem cell products.

Part of the motivation for the draft report was the concern to preserve Europes innovative capacity in the field of genetics, because In Europe, according to a reliable prediction, the genetics sector will grow rapidly over the next 10 to 15 years and become part of conventional medical practice, playing an increasingly greater role in diagnoses and prognoses affecting a persons health. The acceptance of the role of clinical trials as an index of innovative capacity recurs throughout the report. It describes the European contribution to the genetics sector as very significant, both as regards the substantial fund of basic knowledge (30% of publications on gene therapy in the world in the year 2000 originated from the Union) and in terms of industrial competitiveness. The European industry involved in gene therapy is of comparable size to its American counterpart in terms of the number of small and medium-sized enterprises (26 in the Union and 24 in North America in 2000) and large drugs companies (9 in the EU and 11 in the US) but appears to be lagging a little behind as regards the number of employees, the number of sponsored clinical trials, and the number of companies quoted on the Stock Exchange (4 as opposed to 8).

The sector has grown spectacularly in the last three and a half years, the report said, noting that attention should be drawn in particular to the increase in the number of clinical trials, companies which organise trials, and joint projects between companies, since this is a clear sign of the sectors maturity.

Nevertheless, it notes with concern, the North American industry is still stronger and more advanced. This finding is true whether the yardstick applied is the number of employees, the number of companies quoted on the Stock Exchange, the number of companies which organise clinical trials, or the number of or amounts of money involved in joint projects. And this applies in particular, it says, to product development in collaboration with certain US companies which organise the clinical trials at the final stages. In Europe only Transgene is in a position to do likewise.

It is a measure of the growing maturity of the clinical trials sector in Europeand of the growing maturity of the European Union institutions in relation to medicinesthat clinical trials received this much attention in these debates. It was not many years ago that the European Parliament, and indeed the European Union institutions on the whole, were largely ignorant of what clinical trials were, and would have been incapable of articulating a single coherent observation on their role and significance. This more informed parliament does not guarantee that all questions relating to clinical trials will always obtain fully informed discussionbut it does suggest that in the battle for understanding, the European drug industry and research community has made some headway in raising awareness of what is at stake.