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Applied Clinical Trials
What to expect from the new leadership and why there's not much hope for an improved directive.
The European Union lurches into another difficult year, with—for the first time ever—the Czech Republic holding the rotating chairmanship for the next six months, and consequently largely responsible for setting the agenda. In addition to coping with the challenges of energy security, climate change, the credit crunch, and constitutional reform, the Czech government has also listed its priorities in relation to health.
The Czech health program includes efforts to provide patients with new rights to high-quality health care across all 27 member states, increased provision for health care workers to move around within the EU, tighter controls on quality and safety in organ transport and storage, stricter measures for infection control in European hospitals, reassessment of the financial sustainability of health care funding, and interoperability of health care information systems.
"What has all this to do with clinical trials?" one might ask. The answer to that question is, "A lot." And for two reasons.
One reason is that the Czech health program also includes some elements directly related to the development and use of pharmaceuticals in Europe—notably, additional support for research into rare diseases; tighter pharmacovigilance systems; and what are officially described as measures to "improve and guarantee the high quality and safety of pharmaceuticals, while maintaining cost-effectiveness."
How far it gets with these proposals will depend heavily on how far it gets with its overall program—not just in health care but in its overall objectives. Because in the EU, hardly anything is dealt with in isolation. Most decisions are made as compromises among many conflicting currents of national opinion and priorities in 27 national capitals.
So if the Czech presidency runs into difficulties in winning support for its measures to overcome the economic crisis or loses face in diplomatic debacles in the Middle East or with Moscow, it will be less able to pursue other elements of its program effectively.
The other reason is related not so much to the Czech presidency's program as to the clearly expressed concerns of the clinical trials community in Europe.
Any hopes that Europe's much-maligned clinical trials directive is likely to be amended and improved received another blow just at the end of 2008. The principal conclusion of many leading European clinical trials professionals is that now the deficiencies in the directive are going to be completely neglected by the EU authorities for years unless there is a major push to bring in the improvements many are calling for.
It was at a major conference in Brussels in December on EU legislation and clinical trials that the evidence of official indifference was exposed. The conference, on the Impact on Clinical Research of European Legislation, was the culmination of the "ICREL" project, funded by the EU itself to provide objective data and arguments about the need for adaptations to current legislation so as to make European clinical research more competitive.
The background is well known. Concerns have been raised by investigators and sponsors ever since the adoption in 2001 of the EU's Clinical Trials Directive (2001/20/EC). Many stakeholders believe that the directive has largely failed in its objective of simplifying and harmonizing the conduct of trials, and has imposed unnecessary administrative burdens and costs.
As the ICREL study confirms, part of the problem is divergent implementation across the EU member states—giving rise to a total of 122 legislative or guidance measures. The result has been inconsistent interpretation of the rules, duplicative demands for information, longer procedures, and differences even over which languages may be used.
The introduction of the directive has been especially problematic for investigator-initiated clinical research, whose advocates insist on the value of independent clinical research for patients, for science, and for more efficient use of health care budgets.
Respected academic researchers told the meeting that the new framework provides little or no visible improved protection for trial patients, has failed to harmonize regulation, and has certainly not improved competitiveness. Instead, it has made international trials more difficult to conduct and has decreased or delayed access for patient to innovative meds.
But the commercial sector is equally concerned, and industry executives have reported recent trends toward more questions, requests for additional data, and increasingly divergent decisions. Sponsors have had to invest heavily in developing new systems to cope with the requirements and have then had to devote resources to much more paperwork related to GCP, contracts with investigators, hospitals and CROs, more complicated insurance issues, and expedited reports.
More guidelines are not the answer, say industry executives. Nor is mutual recognition the solution for clinical trial authorizations. That approach is incapable of supplying the high degree of reactivity, quick decisions, and rapid information flow needed in clinical trial decision-making. As things stand, bioequivalence studies have already moved substantially outside Europe, largely to Canada and Asia, say industry executives.
For ethics committees too, differences in the structure and function are a problem throughout the EU.
Regulatory authorities acknowledge some of the continuing areas of difficulty—notably persistent nonharmonization of requirements on clinical trial authorization dossiers, definitions, safety reporting, and the concept of investigational medicinal products. National assessments of applications for clinical trial authorizations still differ, and there are problems over transparency of decision-making and adequately factoring risk into decisions.
Contrary to the EU intention of attracting clinical trials, there appears to be stagnation, even a slight decline, authorities suggest, pointing also to an increase in rejections of applications for clinical trial authorizations.
Weaknesses identified by the ICREL report itself were similar. The key failings observed in EU clinical trial regulations were the lack of harmonization of procedures, the lack of transparency, unclear definitions, increased workloads (particularly for assessing annual safety reports), and the need to simplify reporting to ethics committees. Initial ICREL findings were that negative outcomes of clinical trial authorization applications had increased, as had protocol amendments. Meanwhile, the scientific and administrative workload rose, with a corresponding rise in costs.
Faced with such an overwhelming body of criticism—much of it echoing criticisms raised a year earlier at the European Commission–European Medicines Agency conference on the impact of the directive—it might have been expected that the EU authorities have some concrete proposals to offer to remedy the defects.
At least two clear lines of potential relief emerged during the discussions at the ICREL meeting. One was angled toward giving the EU measures greater force and consistency by making them binding in detail on all member states, thus eliminating much of the confusion and delay currently experienced. Another possible improvement, it was argued, could come from focusing more on the real risks linked to any trial, rather than following a standard tick-every-box approach for every trial. This would permit more proportionate controls on trials and allow more efficient use of resources.
But no such relief was offered by EU officials at the conference. In fact, not only was there no offer of relief, the message as it came across to many was that there was very little officials could do about it. The directive had been adopted and was in force, and apart from some minor tinkering around the edges with more guidelines, there was little prospect of any improvement in the foreseeable future.
Political considerations have conspired to leave the clinical trials community a victim of circumstance. The five-year term of office of the current European Commission—the EU's civil service—comes to an end later in 2009, so there is virtually no chance of any new initiative emerging from what is increasingly a lame-duck administration.
Similarly, the five-year term of the European Parliament comes to an end in the spring, so the current crop of the EU's directly elected legislators have no time to examine the matter afresh—and their successors will not be in a position to begin to do much before the end of 2009, even if they can be persuaded of the need.
The only other major EU organ—the Council, consisting of member state ministers—will act only in light of promptings from the Commission or Parliament, or, in extremis, of the member state holding the rotating EU presidency. And as already suggested, the nascent Czech presidency has its hands full already, So little can be expected from the Council either.
The net result is that European clinical trials legislation is in a position akin to that of a disease for which diagnosis is now possible but for which no treatment has yet been found. On that basis, the new year may be happy but it is unlikely to be healthy.
Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.