The EU’s clinical trials directive has been a catastrophe but Brussels is keen to make amends
“Arguably the most criticised piece of legislation” the EU has ever produced on medicines. That’s how the European Commission describes its own law on clinical trials, drafted a decade ago in an effort to streamline medical research in Europe.
Designed to cut costs and red tape, it has been a spectacular failure but Brussels is intent on unpicking the damage done by the end of the year.
The directive formally became law amid much fear and loathing in 2004 and with doomsayers foretelling the collapse of doctor-led clinical trials. Hospital research may not have come to an abrupt halt, but even Brussels officials now accept that the legislation has not delivered. Most say it has made things worse.
In conference centres in Brussels and across Europe, doctors, patients, regulators and industry figures have taken turns trashing the directive as part of a thorough review of what went wrong.
Central to these discussions is Dr Ingrid Klingmann of the European Forum for Good Clinical Practice. She literally wrote the book on the impact of European clinical trials rules, having produced the much-quoted ‘ICREL’ report as part of an EU-funded project to assess the directive’s impact on research.
“We now have higher costs, more people involved and longer preparation time for applications without seeing any increase in the number of patients taking part in clinical trials. So we have made all that effort without having much impact on participation rates,” she said told me.
Klingmann canvassed everyone from research ethics committees and medical insurance firms to academic researchers and pharma industry lawyers. “The outcome was very obvious: all stakeholders had to massively increase their staff to cope with the new requirements and the costs of clinical trials have gone up two-fold or three-fold,” says Klingmann.
Bound by red tape
Many of the well-meaning changes heralded by the directive backfired royally. One such reform was to tweak the rules on when EU-based researchers have to report bad reactions from patients taking part in the trial. It was meant to make life simpler but Kingmann says it means notifying the authorities about side effects which are not related to the medicine used in the trial – effectively adding to their paperwork.
The problem for multinational companies and international research consortia is that the rest of the world is sticking to the old rules, using different definitions for adverse events. This means that if a multi-centre trial is taking place in hospitals in Dublin, Denver and New Delhi they must deal with parallel reporting systems – doubling their workload – meaning they might just be tempted to leave Dublin out of the mix altogether.
One of the things the directive was supposed to do was make it easier to conduct a large trial with several centres across Europe. This would bring the twin benefit of allowing the EU to compete with the US – as well as India, Brazil and others – where the scale and relative simplicity of running trials is a major draw; while also allowing smaller countries like Ireland to compete by joining forces with others.
Brian Moulton, Chief Executive of ICORG, the all-Ireland cancer research group, says 80% of trials are based in a single member state, and this figure rises to more than 95% if you count projects with just two sites. The vision of cross-border multi-country trials simply never materialised.
“These numbers sum the whole thing up for me. The vast majority of trials are happening in single member states. What this shows is that the clinical trials directive absolutely failed in what it was trying to do: to put an equalised system across Europe,” he said.
Speaking from a major US cancer conference where ICORG continues to build links and punch above its weight, Moulton says the Americans enjoy a single application system and one-stop ethics approval – a proposition Europe is a long way from matching.
Moulton says the number of trials in Ireland is down since the rules of the game were changed and that Europe as a whole continues to lose ground as pharmaceutical companies scale back their research investments.
This fragmentation, along with the rocketing cost of insurance, and the flight of talented medical researchers has accelerated Europe’s decline at a time when medical innovation is at the heart of Brussels’ industrial and healthcare policies.
“The whole purpose of the directive was to make Europe a more attractive, more streamlined place. Really all it has done is hand the initiative to Asia,” he says.
However, ICORG has taken some positives. Before 2004, Ireland has more than 80 research ethics committees. Every hospital, every third level institution, every clinic had one. Some were active, many were borderline dormant, but most are now extinct.
Today the Irish Department of Health recognises 13 ethics committees which can give the green light to a trial. This means that if a project takes place in Cork, Galway and two Dublin hospitals, a single ethical opinion covers the whole country. Previously, you needed to apply for approval from all four committees – each of which had its own procedures and might insist on changes to the trial protocol. It was a nightmare.
The reform was resisted by some hospitals, particularly those with a strong religious ethos that feared their moral guidance would be replaced by the lesser mores of others.
That, at least, has changed. It could be further improved by putting the application system online but it is progress nonetheless. The directive also clarified the role of “sponsor” of each trial, even though this can add to responsibilities of the principal investigator.
One of the major bugbears for critics of Europe’s clinical trial environment is that it makes life particularly hellish for academics and for consultants with an interest in clinical trials. It is also clear that the directive focuses on trials of new medicines, paying less attention to research on surgical techniques and quality assurance studies.
The increased paperwork has forced companies to hire more staff and spend money on admin that could otherwise be invested in research or taken to the bank. But for some busy doctors it has been enough to turn them off the idea of leading new trials.
The impact hasn’t been quite as bad as some feared, says Siobhan Gaynor of Molecular Medicine Ireland. At the time the new law was being introduced, many were predicting the death of academic research as a result.
“Now of course we know from the [ICREL] report that in fact they did not die, they roughly stayed the same across Europe. However, the costs, timelines and complexity have increased,” she says.
Academic-led research accounts for 36% of all trials in the EU. In Ireland, around 10% of the new trials approved by the Irish Medicines Board since 2005 were “non-commercial”.
“I think we can conclude from these figures that academic clinical research – at least for drug trials – is not conducted here on the same scale,” Gaynor says, adding that it’s difficult to say where this is a direct result of the directive or if other factors come into play.
A country’s size, availability of funding, research infrastructure, and the lack of protected time for clinicians conducting research are all likely to play a role.
The European Commission has spent the bones of two years consulting widely before it publishing its blueprint for fixing the problem this autumn. At every turn, stakeholders utter the word that strikes fear into the heart of Eurocrats: harmonisation.
The reason the directive made this mess messier is that the EU’s hands are tied when it comes to most aspects of health policy. Healthcare is a national competence, although it can be argued that clinical research is also key to industrial competitiveness.
In any case, Commission officials left national governments to interpret the clinical trials legislation as they saw fit – hence the disjointed implementation.
Now, the challenge for Brussels is to be a little more prescriptive without upsetting health ministers and national regulators. In October, it will either formally clarify elements of the existing directive or introduce a new regulation obliging Member States to follow a menu of reforms – thus ironing out inefficiencies and nudging Europe towards a harmonised system.
Getting it right this time matters. It matters to the cancer patient who wants to take part in a trial for the latest medicines; it matters to a healthcare system which wants to keep its more dynamic doctors by offering research opportunities; and it matters to ailing economies and graduates in need of high-end jobs.
Small countries stand to benefit most from a streamlined clinical trials system. Ireland, with its strength in the pharmaceutical and medical devices sector, as well as an educated workforce, has the most to gain.
This article appears in the current edition of Irish Medical NewsAuthor : Gary Finnegan