A Race to the Finish for CTs in Europe?

It's official. Europe's clinical trial applications are plummeting. Patricia Brunko says so. And she is paid to know about these things. As Head of the Pharmaceuticals Unit in the European Commission's health department, you might even say her job depends on knowing such things.

Peter O’Donnell

Brunko spelled out the rate of decline when she addressed a meeting on clinical trials in the European Parliament in early December. In 2011, there were just 3,490 applications for clinical trials in Europe. The annual total has been slipping steadily for five years: from 5,028 in 2007; 4,629 in 2008; 4,619 in 2009; and 4,400 in 2010. But the latest drop—of nearly 1,000–is the biggest registered so far.

No wonder Europe's clinical trial community is a little stressed, and rather resentful of the EU clinical trials rules, which are repeatedly blamed for the fall-off in trial numbers because they are too bureaucratic. The community is extremely hopeful that the promised review of the rules will help fix the problem, and deeply apprehensive that the revised legislation will not, in fact, go far enough in arresting and reversing this alarming trend.

As Europe's woman-on-the-spot in charge of the revision, Brunko offered some comfort to her audience in the parliament. She confirmed that the proposal to revise the 2001 clinical trials directive was well advanced: it was, she said, "on track" to appear in mid-2012. Acknowledging that one factor in the decline in clinical trials being conducted in Europe "could well be the current approach of the directive," she reassured the assembled politicians, academics, patient associations, and industry executives that the draft she was working on aimed at answering some of the criticisms levelled at the current rules. "We have heard your message loud and clear," she said. "We know you want something that is streamlined, simple, and not imposing too many administrative burdens."

Some comfort. But not exactly total comfort. It is necessary "to be aware of the constraints," she warned. "This is the EU," she said—and that means the scope for changes is limited.

There will be no change in scope of the directive, she confirmed, despite many requests to incorporate relative assessment of different therapeutic approaches, including devices or surgery. The EU rules relate only to medicines, she underlined, and revising the directive will not extend its field of application. "What is in the legislation we can try to fix"—but what is beyond the ambit of EU responsibilities cannot be tackled by revising the directive. She reminded her audience that just because clinical trials take place in an international environment, that does not mean that the EU can operate across national frontiers—and still less impose its views on what should be done in the health area. "Each country has its own jurisdiction, which limits what we can do," she said.

Brunko's new year gifts

What the new proposal is likely to contain when it emerges in 2012 may ease some of the anxieties within the clinical trials community. Brunko's list of new year gifts included the concept of a single EU portal that will allow companies to deliver a single application for clinical trials authorizations at a single EU point. This will, she said, be an improvement on the current system where applications have to be made individually to each of the EU's member states—"knocking on 27 doors," as Brunko put it.

For those who have let slip from their memory the option that the commission suggested in its latest consultation document (now almost a year ago), this would allow the sponsor to send the necessary documentation through a single "EU portal" (a "single submission"), administered by the European Medicines Agency, which would distribute the information to the countries where the trial was to take place. Subsequent applications by the same sponsor for authorization of a clinical trial could simply refer to information previously submitted to the EU portal.

Another treat could be a form of coordinated assessment procedure for such single applications, conducted by a scientific committee made up of representatives of all the member states. But Brunko stressed that the precise format still needs to be refined to ensure a balance between coordination and simplicity: "It must be quick and easy, with no heavy bureaucracy. We'd like to avoid the heavy infrastructure and long deadlines required for full coordination," she said. So decisions will be needed over whether to involve all member states in assessing all applications, or to limit engagement to those countries directly concerned. Additionally, systems will be needed to cope with disagreements, she said.

Brunko's list also includes some element of adaptation to risk—although with a sharp eye on robustness of the data. She also held out the prospect of some clearer rules on the content of the application dossier—although this would inevitably be linked to how far the new rules allow for a single submission and a single assessment for multi-country trials.

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Only a proposal

Despite the fact that the EU's much-maligned clinical trials rules are more than 10 years old (and have been virulently criticized for almost as long as they have been in effect), and despite the fact that the European Commission has been consulting repeatedly on how to improve them for nearly half that time, it will not be until mid-2012 that a text emerges. And even then, the text will be no more than a proposal. So no matter how far Brunko and her commission colleagues feel they are able to go to please the clinical trials community, their view will be only one among many once their text is published.

Then member state officials and ministers, members of the European Parliament, and dozens—possibly hundreds—of other interest groups, will need to have their say. It could take another two years before a new rule is agreed upon, and as long again before any new rule comes into force.

However, it is already possible to discern some of the views that will go into that crucible of discussion when it starts later this year. Hartmut Krafft, who is Head of the Clinical Trials Section in the Paul-Ehrlich-Institut in Germany, set out some of his thinking at the same December meeting in the parliament. His views count, because although he underlined that he was speaking in a personal capacity, he is nonetheless a big figure in the informal but influential grouping known as the European Heads of Medicines Agencies. He coordinates its increasingly popular voluntary harmonization procedure for clinical trials, which already provides a one-stop shop for electronic submissions, and promotes harmonized scientific discussion and decision-making among member states. Here applications are rising, from 15 in 2009 to 26 in 2010 and to more than 75 in 2011.

Krafft supports the idea of a single EU portal for applications, but with limits initially on its use (not, for instance, open for trials in only one member state). He also supports the idea of coordinated assessment, although authorizations should remain a national matter, he told the meeting—and the procedure should not be mandatory for sponsors, at least in its early days.

Industry's principal desire is for harmonized content of the clinical trial application dossier, and a single outcome from a scientific and ethical assessment across all EU member states. Christiane Abouzeid,MD, Head of Regulatory Affairs at the UK's BioIndustry Association, and Head of EuropaBio's clinical trials topic group, told the meeting that "of the more than 650 biotechnological medicines undergoing clinical trials, many are produced by smaller firms, which feel the administrative burden of the diverse implementation by member states of the current rules."

But the industry is also nervous of the risk that the new rules may seek harmonization through accumulation. Abouzeid emphasized that it would not support a solution if the clinical trial application dossier came to consist of a list of all the current national requirements. "It is essential that extending clinical trials to multiple member states does not trigger a costly and burdensome repetition of the scientific assessments by the different regulatory authorities."

Detlef Niese, Head of Global Development External Affairs at Novartis Pharma AG, and Vice-Chair for Science of EuropaBio's Healthcare Council, adding his voice, also focused on the obstacles currently faced by small firms, which, he underlined, generate many valuable new candidate therapies.

Patients too want greater harmonization, and the European rare diseases campaigning group, Eurordis, is backing single assessment of trials, and arguing against diversity of approach merely to meet the wishes of distinct national ethics committees.

Now the big question is whether the EU will be able to move fast enough with its new legislation to improve the environment before Europe's clinical trials activity plummets still further, or even disappears altogether. Brunko and her team have more than their jobs to protect. If they get it wrong with their proposal, a lot more jobs in Europe are going to disappear too.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.

Benefit from industry updates and case studies related to this article

Forum on Global Publication Planning & Clinical Trial Registries

Strategies for Effective and Compliant Data Dissemination and Coordination

June 11-12, 2012

Amsterdam, Netherlands