The European Commission's Clinical Trials Directive was meant to make trials more simple. But it looks as if the effect has been to stop many trials taking place at all.
A meeting in Princeton, New Jersey, next week, aimed at representatives from the pharmaceutical industry, will debate a topic that has become depressingly familiar over the past 12 months: whether Europe is still an attractive venue for conducting clinical trials of new drugs in light of new EU legislation and competitive options to be found in Asia, Africa and Australia. The question is one that European researchers have - perhaps too late - begun to ask themselves, and so far, the answers are not encouraging.
The problem stems from the layers of additional research regulations and legislation that have been introduced across Europe over the past five years.
Intended to protect the rights and safety of patients, to simplify and harmonise the administrative procedure, make trial conduct more transparent and guarantee the credibility of results, the new regulations have introduced so much red tape that the increased administration needed to comply with them has driven research costs up by 85 per cent says Patrick Therasse, director of the EORTC (European Organisation for Research and Treatment of Cancer) Data Center in Belgium. And the chief culprit of the regulations is the EU Clinical Trials Directive (2001/20/EC), introduced on 1 May 2004.
According to Therasse's calculations, the number of clinical trials initiated annually in Europe has declined by 70 per cent over the past decade - tumbling from 27 to 7/8 in 2005. The steepest decline occurred after the directive was published in 2001. Those experiencing the least decline are France and the Netherlands, which have still not integrated the requirements of the directive into their national legislation.
Academic trials halved
Therasse's figures resonate with those of cancer researcher Markus Hartmann, who recently undertook a study of the effect of the directive on academic, or non-commercial, research in oncology during the first year of its implementation. Hartmann told Science|Business that trials conducted by academic institutions halved between May 2004 and March 2005.
"Since the implementation of the clinical trials directive, the EMEA register shows that of the 3,000 trials registered, only 14 per cent were non-commercial. That's a drop of 50 per cent over the first year after implementation," he says. His says his figures tally with those of the UK's National Cancer Research Network, which reports a drop of 40 per cent for non-commercial research trials, and those of the chairman of the German ethics committee.
However, Kent Woods, Chief Executive of the UK's Medicines and Healthcare products Regulatory Agency (MHRA), questions whether the decline is permanent. One reason is that academic researchers in the UK who were eligible for a clinical trials exemption certificate were encouraged to apply for this in advance of the directive’s implementation: "Many researchers applied early for their trials exemption, as we advised them to do, so we weren't surprised by the dip in the first few months after the new regs," Woods told Science|Business. "The key question is whether this is a transient or sustained reduction in new trials."
In addition, Woods believes that duplicative trials and those of
borderline quality will be discouraged by the more formalised process
of applying for a clinical trials authorisation, and this too will
translate to a drop in the number of trials. "The difficulty is that
several changes have happened simultaneously in the UK. In addition to
the clinical trials directive, there are also the research governance
requirements from the Department of Health, plus changes in the ethical
committee system. We need to know which, if any, has affected the rate
of initiation of new trials."
The MHRA has commissioned the UK Clinical Research Collaboration to gather information on the number of trials being initiated to determine whether the directive is impinging on research. The first report was presented to the MHRA board this summer, but it was inconclusive. "We didn't have enough data and we need more," says Woods.
Cancer hardest hit
The reason the directive is causing so much trouble, say academic researchers, is because it is designed to address the needs relevant to licensing new drugs - and therefore the type of trials run by industry. It does not take account of the constraints of non-commercially funded clinical research. "Industry have said to me that they can cope with the directive," says Woods. "However, the non-commercial sector has a different set of concerns."
There is no allowance for the different types of trials that non-commercial investigators conduct, such as analysing different regimes of already marketed drugs, or non-medical interventions like surgery, or comparisons of the two. As this describes a substantial amount of oncology studies, the field of cancer research has been hardest hit. And seeing as at least a quarter of all non-commercial trials in Europe are cancer studies, according to Hartmann's data, this explains why academic trials have dropped so sharply.
Therasse is hoping for some leniency for non-commercial research when the Good Clinical Practice add-on to the directive is published in January 2006. The EORTC has lobbied for a special clause to be included in the good clinical practice document specific to non-commercial clinical trials because of its huge public health benefits. But although member states will technically be allowed to revise their legislation under the good clinical practice directive to give more freedom to academic research, the chances that they will take the trouble do so are slim.
According to the scenario described by Hartman, orphan diseases will suffer more than other fields because of the directive. "Running a running clinical trial throughout the European Union will cost you the same, more or less, if there's ten patients or a hundred because you have to do documentation, a yearly report and adverse events for each member state. So the financial burden will become so high that for these indications it will be too difficult to run trials," he told Science|Business.
Hartmann added: "I expect that even if the total number of clinical trials only drops by 20 per cent, then the number of international trials will drop considerably - more than 50 per cent - and because of the clinical trial directive’s failure to achieve harmonisation of documentation. In short, the European directive will destroy pan European research. It'll no longer be the place for the multicentred trials that we had in the past."
Despite such serious ramifications, and even though the directive was published in 2001, investigators across Europe have been slow to comprehend its significance. A survey of 10,000 European cardiology researchers this summer showed that 42 per cent of them were still not aware of its existence. A further 44 per cent had heard of it but still responded that they didn’t know much about it. Of those who said they were "well aware" of the directive, 42 per cent thought it would decrease they number of studies they perform, with the majority forecasting a drop of 25 to 75 per cent. Three-quarters thought it would increase cost, largely due to administrative load, and half thought it would increase quality.
Thus, at a time when several pharma companies are starting to move research out of Europe to the US, India and other parts of the world where the costs research and clinical trials are a fraction of those in Europe, it now seems that the hub of academic research is set to follow.