Trial and Error—Europe's New Rules Inch Forward

No apologies for returning—yet again—to the discussions over Europe's attempt to bring its clinical trials rules up to date. Whether the current proposals are adopted or not, these discussions are likely to define the context for clinical trials in Europe—and beyond—for many years to come. And since the discussions are happening as I write—and still happening as you read—no one will be entitled to lament the outcome if they neglected the chance to make their voices heard while it was still in the design phase. The timetable currently foreseen in the European Parliament is that the health committee will debate the plans in late April, and will finalize its view with a vote on May 29. Then the Parliament as a whole will take a view in early October.

Intensive lobbying of the most influential members of the European Parliament is underway from all sides—and some of them are playing hardball. Among the latest into the fray is a new coalition claiming to represent researchers, doctors, scientists, patients, and civil society. This is campaigning vigorously for strong transparency provisions in the new rules. The coalition includes health activists such as HAI-Europe and the TransAtlantic Consumer Dialogue (TACD), as well as organizations prominent in critical drug review, including the Cochrane Collaboration and the International Society of Drug Bulletins.

They argued, at a recent hearing in the European Parliament that was organized by the lead MEP on the subject, Glenis Willmott, that the complete clinical study report should be subject to public disclosure. The proposal, as it stands, requires a publication of a "summary of trial results" within a year of the end of the trial. They also rejected any strengthening of protection for "so-called 'commercially confidential' or 'commercially sensitive' information"—a move which would be "a major step back and undermine the accountability of the European pharmaceutical regulation system," they said.

This coalition claims that "half of all clinical trials are never published," and of those that are, "only a selection of positive results, from which important harms may have been omitted, are disclosed." They go on to suggest that "numerous recent drug disasters would have been avoided if public access to clinical data had been granted." They dismiss the proposed compromise of publishing a summary of clinical trial results as "of little scientific value," leaving researchers without "the information they need to judge the merit of a trial."

Industry representatives have been arguing that it would not be helpful to publish clinical trial results for a treatment which has not even been assessed by the regulator, since the results of just one of several trials, taken out of context and while the drug is under development, provides only one element rather than the full picture.

The European Organization for Research into Cancer (EORTC), also present at that hearing, says that it fully supports transparency. But its head of international regulatory affairs, Anastassia Negrouk, told Applied Clinical Trials that there needs to be a lot of careful thought about how to make information available, what sort of information should be made available, to whom, and for which purpose.

"We fully agree on the obvious and essential need for transparency," she said. But, she pointed out, "not all clinical trials are done with new drugs, for which a registration dossier will be filed with the European Medicines Agency." She also cautioned against the risks of accidental exposure of personal data through injudicious disclosure. For instance, she said, the ICH E3 format—one of the standard reporting formulas—"contains listings of individual patient data which are usually coded—but may still be at risk of identification in some cases." This risk should be carefully assessed before any decision to make such reports freely available through the web, she said.

A representative of TACD focused on the inherent risks of conflict of interest when health and money are mixed up. He insisted that no research organization can be trusted to be unbiased if it receives any funding from the pharmaceutical industry. On this too, EORTC took a more nuanced position. "We always insist on independence, but we partner with industry because it is industry that manufactures medicines, so there is an obvious need for a reliable partnership." EORTC supports transparency over conflict of interest declarations, "but it is not realistic to expect that no clinical trial experts, even within academia, would have any conflict of interest."

Another recent hearing looked particularly at the German aspects of the debate. Hosted by German MEP Dagmar Roth-Behrend, the participants included academics, patients, and the German pharma association VFA. This highlighted—again—the deep concerns in Germany about the absence of explicit references to ethics committees in the proposed new rules. Professor Jörg Hasford, President of the Working Group of German Research Ethics Committees, underlined the need for greater consideration for ethics review. He added that reviewing applications in English—which could be one of the consequences of the new rules—will be a challenge for many ethics panels.

Some optimists see this strong German concern as a possible lever to promote more cooperation among ethics committees—nationally and at a pan-European level. The evident and long-standing lack of systematic cooperation is one of the reasons that clinical trials in Europe still labor under an administrative burden. Stefan Führing, the representative of the European Commission at the meeting, defended the proposals, and repeated the commission's position that it is not for the European Union to impose anything in terms of ethics review, since this is a purely national competence. In addition, he said, national review is organized very differently in each member state, and the commission cannot dictate a model for the whole of Europe.

Meanwhile, the EU Council of Ministers also has to decide how it is going to respond to the proposal. Frequent meetings are taking place at the level of national officials, and they are finding plenty to criticize in the detail—but their role as officials is only to prepare the ground, rather than to take a view. That is the job of diplomats and, ultimately, ministers—and that remains a long way ahead at present. This columnist raised the subject in mid-April with the senior diplomat in Brussels in charge of these areas of EU business—Ambassador Tom Hanney of Ireland (Ireland is the current holder of the rotating six-month presidency of the council). Hanney was polite, but he made it clear that it was really not on his radar yet. "This is not something the Irish presidency expects to conclude discussions on," he said modestly, suggesting that it may be more a matter for political decision-making for the Lithuanian presidency (which starts in July) or even the Greek presidency (in the first half of next year).

The reality is that if some form of the proposal doesn't get adopted by both the Parliament and the council by next spring, it is at risk of dying away entirely, because the Parliament has just decided to close early next year. This is not a fully frontal attack on the clinical trials directive. This piece of legislation barely registers among the many other issues that Europe is confronting. The reason is more related to high politics than to deep science. The Parliament was due to hold the final session of its five-year term in May next year, before elections across Europe are held to choose the next crop of MEPs for the next five years. Over the last few weeks, the Parliament has agreed to hold its final session in April so that the elections can take place in May—allowing time for the new Parliament to exert, it hopes, some influence over the appointment of the next president of the European Commission. And what doesn't get agreed before parliament dissolves is likely never to be heard of again.

At the political level, there is really only one factor that could play in support of pushing the work on clinical trials to a conclusion. And that is the sense of mild embarrassment, among the people who run Europe's business, that the scorecard in medicines legislation is pretty thin over recent years. New rules were passed on pharmacovigilance and the fight against counterfeiting. But the controversial proposal on information on medicines has been swallowed up in the smoke drifting across the battlefield it created in Europe over communicating with the public. And the other conspicuous failure is the attempt to modernize the limited controls that the European Union has over national pricing and reimbursement systems, currently struggling to survive in a revised form in the face of hostility from national governments. The clinical trials rules could emerge as figleaf intended to conceal the shameful lack of EU strategy for pharmaceuticals.

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