Gathering ?Buts? in May

The passing of the EU Directive deadline next month is unlikely to quell the stormy debate over its far-reaching impact.

The traditional childrens Mayday song of Here we go gathering nuts in May could well be drowned out this year by loud expressions of buts rather than nuts. May 1 is the deadline for implementing Europes new clinical trials rules, and growing concerns over the impact on clinical research are going to ensure the date does not pass unremarked.

Many of the anxieties that have underlain the 10-year genesis of these rules remain unresolved, even in the final weeks before the rules are due to come into effect across the 25 member states of the European Union. Most notably, in an appeal to the authorities for more understanding, nearly a thousand scientists and doctors from 33 countries around the world have signed up to an expression of concern over the impact the new rules will have on their work.

From Australia to Serbia, and from Egypt to Norway, 837 specialists with experience of multicenter international trials conducted by academic clinical research organizations have argued that important problems for academic research have not been adequately addressed.

The appeal, orchestrated largely by the European Organisation for Research and Treatment of Cancer, focuses attention on the way that the EU Directive on clinical trials poses threats to vital aspects of noncommercial clinical trials.

Specific difficulties are anticipated in relation to sponsorship: the pharmaceutical industry may not be willing to provide its products for noncommercial trials if this is perceived by competent authorities as some sort of sponsorship of the trial.

More generally, the directive is expected to result in increased administrative work and expensesuch as fulfilling requirements on on-site monitoring, or through fees to ethics committees and authorities. The fundamental anxiety is that the directives focus on commercial clinical research is ill-adapted to the realities of noncommercial research and will impose intolerable burdens on the scientific community, leading to the discontinuation of much valuable work. If implemented without caution, the Directive will prevent important research from being conducted, the appeal states.

The blind implementation of the directive in Europe could drain the interest for research in the health care sector with more research being conducted outside of Europe. This is already the case for commercial research (drug development) and EU member states are about to set the rules to also push noncommercial research away from the European area, warns Patrick Thrasse of EORTC.

In support of its case, the appeal cited examples of important clinical trials which would not be conceivable under the future legislation. The data for this approach come from a January 2004 snapshot review by the EORTC of all its trials recently closed, currently open, or about to be activated. The review projected the consequences of the directive on this set of 127 clinical trials, and found that in the worst case scenario, if the directive was strictly implemented, approximately 60% of all academic drug trials would not have taken place.

This translates into a significant amount of critical research no longer being conducted and important improvements in health care would not have occurred, the appeal continues.

Worse, although this embarrassing situation is recognised by the European Commission as well as by the legislators in most member states, no real solution has yet been proposed, it says.

With characteristic resourcefulness, however, the signatories to the appeal have come up with a possible way out of the jam. While it is too late to repeal the directive itself, which has been adopted by the EU member state governments, the appeal suggests that changes should be made to the detailed notes for guidance produced by officials in the European Commission, which deal with the practical implementation of the directive. These can be amended at any time and national authorities have some flexibility in the implementation of the text, the appeal argues.

A possible solution
The appeal even offers a trial product for evaluation: the Belgian approach to implementing the rules. In Belgium, the appeal says, constructive interaction between academia and competent authorities has resulted in a national implementing text that addresses some important problems identified for academic clinical research. Above all, the Belgian text makes some explicit provisions for excluding academic research from the most onerous requirements of the directive.

The signatories to the appeal want all EU member states to urgently consider the Belgian proposal as a model, so as to avoid blocking most academic clinical research. All national legislation should provide special conditions for academic noncommercial research, including simplified procedures and conditions for using marketed drugs. They say this could form a basis for a harmonization at the EU level of the application of the Directive for academic research. They also urge specific corrective detailed notes for guidance to be developed to address other problems faced by academic research. And they would like to see formal dialogue between academia, industry, competent authorities, and the European Commission to cover the way this directive is implemented and the drafting of any new legislation in this area. Academia needs to be formally represented directly and indirectly in talks with the commission, they insist.

There is a problem
Some of the concerns over the impending implementation of the directive have already percolated through to the EU institutions. In discussions in February in the European Parliaments committee on environment, public health and consumer protection, U.K. member and committee chair Caroline Jackson raised the diffi-culties facing noncommercial research.

The Irish government, which holds the rotating Presidency of the EU for the first half of 2004, said it was fully aware of the problems with this directive, and that it had received comments from research institutes operating in the area of cancer. Nothing should undermine this kind of research, says the responsible minister, promising to raise the matter with the European Commission in order to get clarity and ease the concerns.The coming weeks will show how far the Irish Presidency can act on its promise.

Taking the clinical battle abroad
Meanwhile, the EU is continuing its efforts to mobilize clinical research that could more effectively combat diseases in developing countries. During February, European Research Commissioner Philippe Busquin followed up his visit to southern Africa last year with a trip to Senegal, for the formal launch of the E600 million European and Developing Countries Clinical Trials Partnership program that the EU has been promoting.

The visit also aimed at encouraging West African countries to join the initiative, in which the EU is funding clinical trials, and fostering clinical research in developing countries. The EU has pledged E200 million, with a focus on the three major poverty-related killer diseases of sub-Saharan Africa: AIDS, malaria, and tuberculosis. Another E200 million will come from EU member states, and a further E200 million will be funded by other international donors and industry. The EU is also devoting E200 million to basic preclinical research in this field.

Research into treatments for diseases does not just mean working in laboratories; it also means working with the sick and infected in their own communities, said Busquin before he left Brussels. By visiting Senegal, one of the exemplary countries in the fight against HIV/AIDS, I hope to highlight what the clinical trials program means in real terms: European countries working in partnership with developing countries and the pharmaceutical industry to reduce suffering and poverty.

SIDEBAR: Studies that the Directive Would Have Prevented
Some of the EORTCs examples of trials that would have proved impossible if the proposed rules were already in force:

• A pyriform sinus cancer study demonstrated the benefit of a neo-adjuvant chemotherapy to reduce the tumor burden before surgery and enable the preservation of the larynx during the surgery without compromising the long-term survival of patients. Since this trial was published, patients operated can keep their natural voice instead of having to speak with artificial means.
  
• A randomized trial of two regimens of chemotherapy in operable osteosarcoma demonstrated that the administration of a 2-drug regimen as opposed to a complex 10-drug regimen (which was the standard treatment) was shorter in duration, better tolerated, and as efficacious. Beyond the clear benefit for the patients, this trial also illustrates the possible economic impact academic trials may have for the societythe appeal arguespointing out that for obvious reasons, no pharmaceutical company will ever support such initiative.
  
• And a study of the effects of concomitant cisplatin and radiotherapy on inoperable non-small-cell lung cancer demonstrated that the combination of radiotherapy and cisplatin (a marketed drug for other indications) increased significantly the overall survival of patients as compared to the standard treatment, which was radiotherapy alone. Cisplatin in this setting has been used to increase the sensitivity of tumor cells to radiations. The dose of cisplatin used in this setting is largely inferior to the dose normally prescribed in other malignant indications for which cisplatin is used as a cytotoxic agent. However, in this trial cisplatin is used outside of its registered indication.

If the drugs used in these studies (all of them being marketed for other indications) had to be provided by the researchers, the studies would not have been possible, says the appeal. And if other conditions required by the new legislation had applied, at least one and probably two of these trials would not have been conducted.POD

SIDEBAR: Inside the Black Box of EU Rule-Making
Nothing is simple in EU rule-makingleast of all when it comes to clinical trials. But the essential features of the EUs complex system can be summarizedas follows:

• The perception of an EU legislative void or incoherence can trigger action by the European Commission (the EUs principal administration) to propose new rules. There was (and is) plenty of incoherence in national rules on clinical trials in Europe, so the commission started drafting a directive in the late 1980s.

• A formal legislative proposal (such as a directive) from the Commission is examined by the EU Council of Ministersthe formal representatives of the member states governmentsand by the European Parliament. They can (and usually do) amend the initial proposal, and they can even reject it. The clinical trial draft directive went through numerous changes during its lengthy review by council and parliament before it was finally adopted in 2001.

• When a directive is adopted, it still has to be transposed at the national level into the legislation of each of the EU member states; the directive fixes the objectives to be attained, but leaves it up to each member state to find the precise legislative tools to attain the objectives. A transitional period is invariably allowed for this stage of the process. For the Clinical Trial Directive, the deadline for implementing the directive is 1 May 2004.

• Some directivesparticularly those dealing with complex technical subjectsare accompanied by guidance from the European Commission, aimed at ensuring effective and accurate transposition throughout the widely differing legislative frameworks of the 15 (and from 1 May 2004, 25) member states. For the Clinical Trial Directive, more than a dozen such guidance notes have been created by the commission. These guidance notes do not have the force of law, and can be relatively easily updated and modified as circumstances dictate.

• After the implementation deadline has expired for a directive, the European Commission checks on whether the member states have fully and accurately put into effect the new rules they signed up to implement. If it finds noncompliance, it can (and does) take legal action against offending member states requiring them to implement the rules properly. If member states still do not cooperate, the commission can drag them before the European Court of Justice, which may impose fines if it concludes that a member state is failing in its obligation to implement the rules. For the Clinical Trials Directive, none of this checking can even begin before 1 May 2004and action is often painfully slow, with delays of years before recalcitrant member states are brought into line.POD