Getting Efficacy into European Trials

Europe remains as challenging as ever for clinical trials, but also for everyone trying to make sense of Europe as a political entity. The jumbo meeting on clinical trials at the European Medicines Agency in early October—on which a report appears at —provided further evidence of just how complex life can become in the European Union. This unique organization binds 27 member states together tightly, voluntarily, legally—but not completely. And the conduct of clinical trials is one of the activities that keeps slipping between the gaps in the curious configuration of EU rules, which resemble wickerwork more than cast-iron.

Peter O'Donnell

This is not the place for a lengthy disquisition on the constitution of the EU. Suffice it to say that the 27 member states not only disagree with one another on clinical trials regulation, but that even where they do agree in principle, they frequently disregard at national level the rules they have created at the European level.

At the end of the meeting at the Agency, Georgette Lalis, the senior official from the European Commission, openly acknowledged that the majority of member states just do not comply with the guidelines they have signed up to on clinical trials. Worse, under the system in force, there is no way that either the European Commission—supposedly the watchdog of compliance —or the Agency can do anything to oblige member states to comply.

Thomas Lönngren, the executive director of the European Medicines Agency, told Applied Clinical Trials that it was outside his powers. The Agency handles only some of the technical work on clinical trials, such as site inspections and databases, he insisted. "It is not involved in clinical trials legislation. That is in the hands of the member states and it is their responsibility," he underlined. And, he made clear, it will require "a political decision" to change the system.

EU Documents Set for Release in Early 2008

Undiminished energy

Nonetheless, the key clinical trials experts at the Agency have, meanwhile, been looking ahead with undiminished energy. The Agency's efficacy working party has just agreed on its workplan for the next two years under its chairperson Dr. Barbara van Zwieten-Boot of the Netherlands. In terms of direct contact with individual sponsors, it expects to provide support in terms of scientific advice on 15 occasions each year, protocol assistance five times a year, product assessment six times a year, and postauthorization pharmacovigilance issues related to a product or a class of products just twice a year.

But the bulk of the work will, as usual, consist of the generation or revision of guidelines for efficacy testing. The ones to watch out for particularly are those still in the consultation process because there, everyone in the clinical trials community has a chance to influence the outcome. The first quarter of 2008 looks like it will see a volley of consultation documents released. A revised draft on clinical development of medicinal products for treatment of HIV infection is expected to be released for consultation in early 2008, following the adoption of a concept paper last February. So too are drafts of new guidelines on the clinical development of medicinal products for tuberculosis and Hepatitis C, now that there has been time to digest comments on the concept papers adopted in April 2007 (see Table on page 38 for a list of other consultation documents expected to see the light of day next year).

No cynicism

A cynic might be tempted to discourage the clinical trials community from getting involved in a discussion of these guidelines if the member states are not going to take them seriously. But cynicism has no place in Europe—or in this column. In general, the guidelines from the efficacy working party have tended to harmonize thinking—among regulators as well as sponsors—on new medicines development. The conspicuous member state noncompliance at present relates to the detailed guidance on methodology for the conduct of clinical trials in line with good clinical practice.

Cynics might also interpret the delays in another EU policy as evidence that it is going adrift. The Innovative Medicines Initiative (IMI) is taking on the appearance of a mythical beast—frequently referred to, but never seen. This is the partnership-in-the-making between industry and the public sector to boost pharmaceutical research and speed valuable medicines through to market. It is invoked at every pharmaceutical-related meeting in Europe as a panacea for all ills—but it still hasn't happened.

The IMI is one of six so called "Joint Technology Initiatives" introduced in the EU's new research support program, aimed at bringing together universities, hospitals, public authorities, patient organizations, clinical centers, and pharmaceutical companies to boost biomedical research and the development of new therapies. The idea is that it will create partnerships through open calls for tender, with the main focus on precompetitive pharmaceutical research—tools to make early and reliable predictions on safety and efficacy of candidate products. Priorities will be treatments for diseases like cancer or Alzheimer's, and the total budget will be o2 billion ($2.8 billion) for 2007 to 2013—half from the EU budget and half from research-based pharmaceutical companies, in the form of staff, laboratory equipment, and clinical research. The EU funding will go exclusively to smaller firms, nonprofit organizations, academia, authorities, clinical centers or patient organizations, but not to big companies.

Blessings and bottlenecks

Recently, EU ministers gave another blessing to the concept. But the European Parliament, which has to give its opinion on the exercise, is taking an uncommonly long time to get around to even a preliminary discussion of the proposal. The French MEP appointed by the Parliament to prepare its opinion, Françoise Grossetête, has still not managed to produce an initial working paper—and requests to her office for information about the drafting are stonewalled.

Things are moving faster (though no less bizarrely) in another Parliament committee that is merely offering a secondary view. Dagmar Roth-Behrendt's draft welcomes the concept of support to the development of high tech medicines, but it also insists that research into herbal and nonprescription medicines should be included too.

Meanwhile, so nervous are some pharma industry organizations becoming about the entire project that they too are clamming up, refusing to divulge not only how far they have gone toward joining the project, but also ducking questions about where they find difficulties with the proposal. "We don't like to say anything about it to outsiders," darkly muttered the spokesperson for one high tech research organization, "because every time we raise any criticism we get into trouble with the EU authorities."

Now, about that constitution...

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