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European Commission's proposed system faces scrutiny from three separate committees.
Be careful what you wish for" is a thought running through the minds of many people in the clinical trials community in Europe these days. There was wide rejoicing when an energetic campaign to replace the European Union's unloved 2001 clinical trials rules persuaded the European Commission last year to propose a radical new system that looked as though it might simplify the current procedures. But in the European Union, the commission only proposes. It is the EU legislative apparatus that disposes. And as the proposal makes its way through the arcane mechanisms of the European Parliament and the council, it might be said that the radical new system envisaged by the commission decomposes.
In late February, the European Parliament took its first look at the draft legislation. Three committees are examining the text—and plenty of their members are already trying to pick big holes in the radical simplicity of the commission's proposal.
The Health Committee has principal responsibility for the subject, and it chose a UK socialist, Glenis Willmot, to lead the discussions. She has produced a report that damns the proposal with faint praise. A more streamlined approach may be alright in principle, her report suggests, but the commission has gone too far in trying to make it easier to conduct trials. "The well being of individual research subjects must take precedence over all other interests, and therefore has to be emphasized more in this legislation," her report offers, right at the start.
So at a stroke she seeks to reverse one of the key elements in the commission's proposal—the revolutionary concept of requiring each national authority to deal rapidly in their own way with local matters, including the views of the Ethics Committee. This is central to the commission's approach, aiming to relieve sponsors of the burden of winning agreement from multiple committees in numerous countries each time a trial reaches across borders.
The commission has proposed this approach as a neat way of avoiding the minefield of distinct national ethical reviews. But Willmot sees it as ducking the issue. For her it is not enough that trials should now be subject only—as the commission proposes—to "prior authorization," with whatever national procedures are required for obtaining such authorization. She wants to add an explicit provision requiring "prior approval by an ethics committee," on the ground that this "is a necessary condition for any clinical trial." And she wants a provision made for cooperation among member states on ethical issues and informed consent. In other words, she dismisses the commission's attempt to cut through the Gordian Knot of diverse Ethics Committee views and approaches by relegating such discussions to a purely national level, and leaving it out of the EU rules.
She is not indifferent to the problems. She recognizes that the current ethics review procedure "is a source of delays and fragmentation," because it "varies greatly between member states, often with various bodies at national, regional, and local levels, and multiple procedures leading to divergent assessments."
But in her view, a new rule that merely requires each national authority to reach a view on all aspects of an application—scientific and ethical—could expose trials subjects to risks. So for Willmot, the rules should insist that member states "ensure the involvement of an independent ethics committee"—and she goes on to enumerate the appropriate composition, including healthcare professionals, lay persons, and patients or patient representatives. The solution, for Willmot, lies not in demanding that each national authority sort out its own approach and come up with its own view, but in more European discussion of ethics. "In the interests of European patients and public health, the procedures and principles of ethical review should be better harmonized through the sharing of best practices between ethics committees." The commission should be aiming to overcome the problems, not dodge them, she suggests. It should "facilitate the cooperation of ethics committees."
Her views on the commission's proposal also emphasize the need for tighter controls on sponsors—they "should be required to provide the rationale of the decision to withdraw an application," to prevent them from "shopping around" for clinical trials authorizations —and for greater disclosure. "Clinical trial data should not be considered commercially confidential once a marketing authorization has been obtained," she says. "Once a clinical trial has led to marketing authorization, data generated during the clinical trial should be fully accessible."
She also wants "reinforced guarantees with regard to the independence of the persons assessing the applications," the same standards for clinical trials in non-EU countries as in the European Union, publication of a comprehensive clinical study report, and penalties for sponsors that fail to meet deadlines for providing it.
If there is an undertone of distrust of the clinical trials community in the Willmot approach, it rises clearly to the surface in the report prepared for another of the Parliament's committees.
French left-wing MEP Michèle Rivasi told the Parliament's Committee on Research and Industry that the proposed new rules will not protect patients sufficiently—as demonstrated by experience with Servier's Mediator, Merck's Vioxx and GSK's Seroxat. She particularly opposes a provision which would ease controls on low-intervention clinical trials—a key element in the commission's proposals.
The commission proposed that low-intervention clinical trials "should be subject to less stringent rules, such as shorter deadlines for approval," because of their importance in assessing standard treatments and diagnoses and "optimizing the use of medicinal products." Rivasi is urging fellow committee members to seek deletion of this provision. She says it opens the door to risky post-marketing authorization studies. "Where the authorized investigational medicinal product is subject to a post-authorization study, it takes place just because of a suspicion of insufficient efficacy or of an additional risk to patients' safety compared to normal clinical practice even if it used in accordance with the terms of the marketing authorization. It was the case of the Regulate study using benfluorex (Mediator), and of the Vigor study using rofecoxib (Vioxx)," she says.
Her draft opinion for the committee also urges greater transparency over trial data, to avert the problems that, she says, arose with Seroxat. Rivasi says that a new database should contain much more information on each trial than proposed by the commission. She proposes that it should include a clinical trial report with a statistical analysis plan and details of the protocol and raw data, in easily searchable form. In addition, "all personal data of data subjects participating in a clinical trial should be anonymized in the database and the information should be public."
Her justification is that non-disclosure of detailed results impairs scientific knowledge and leads to publication bias, with negative findings not published. This "paints an inaccurate picture of a medicine's effectiveness. For example, publication bias led to the wide use of the antidepressant paroxetine (Seroxat) in children and teenagers despite a lack of effectiveness and more worrying despite an increased risk of suicide in this population," she says. Rivasi's insistence on better access is based on her view that "clinical trials data are scientific data, which are gained from the inclusion of the public and which have significant impacts on the public. They therefore belong first and foremost to the public. Submission of a summary is not sufficient to protect patient's rights and interests."
Rivasi also says the commission proposal goes too far in trying to remove widely-criticized barriers to clinical trials in the current legislation. "High standards of care and treatment of patients must be upheld," she said, "and not lost in efforts to simplify procedures." She speaks of her "fears" of weakening "respect for human rights, patient safety, and high standards of ethical scrutiny." Like Willmot, she rejects the commission's proposal to omit explicit reference to Ethics Committee approval, and insists that clinical trial authorizations must be contingent on the decision of an independent ethics committee. And to "ensure the trust of patients" in controls on clinical trials, she reinforces Willmot's call for fines for non-compliance. When companies fail to supply final reports on trials, they should pay "up to 7,000 euros for the 30 first days of non-compliance and up to 7,000 euros per each additional delay day until compliance," she recommends.
A third report, for the Parliament's Consumer Protection Committee, has been drafted by Romanian liberal Cristian Busoi. This is much more supportive of the commission proposal, and in some cases goes even further than the commission in its ambitions to streamline clinical trials procedures. For instance, Busoi recommends that updates to the investigator's brochure should be required only when necessary, because new information has become available, instead of an annual obligation.
The Parliament as a whole is expected to reach a view on the proposal before the summer break. Meanwhile, national authorities are also meticulously dissecting the proposal in the council, and so far the clear consensus from these discussions is that some form of Ethics Committee approval will have to be reinstated in the new rules if member states are to sign up. The chances of a clear run for streamlined clinical trials procedures grow dimmer by the month.
Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.