Change the CT Rules, but to What Precisely?

The European Union is going ahead with the review of its clinical trials rules, and many of the key figures in the European clinical trials community are worried that time is running out for them to influence the way the debate on the new rules will shape up.

Peter O'Donnell

Everyone agrees that some change is needed to the rules. The question is what sort of change, and how much of it. European Health Commissioner John Dalli has clearly indicated that he wants new rules: "If we want to continuously stimulate pharmaceutical innovation in Europe and give patients access to the most recent healthcare, we will need to revise our legislation on clinical trials," he said recently. He acknowledges that the current framework "has led to complicated procedures, in particular for multi-national trials." But he has not indicated how he aims to remedy this.

Right now his staff is working on an assessment of different options for changes, and by early next year a legislative proposal is scheduled to appear. This will then go into the EU's legislative machinery, where it will be kicked about by the European Parliament and by national ministers of health meeting in the EU Council—who, between them, may accept, amend, or reject the proposal.

Fixing deficiencies

Many in the clinical trials community in Europe are nervous that the deficiencies that they have suffered from since the current rules were adopted 10 years ago will not be fixed, and that the legislative process may deliver something not much better than the existing framework, or even make it worse. One of the main fears is that new rules will not prevent each country from continuing to insist on its national mechanisms, invoking "cultural differences" and similar arguments for ducking out of a European approach.

This is why the European Forum for Good Clinical Practice (EFGCP) and the European Organization for Research into Treatments for Cancer organized a joint meeting of interested parties in Brussels in July. "We cannot afford this nationalism anymore if we want to rescue clinical research for Europe," said the background papers for the meeting. According to Ingrid Klingmann, the EFGCP chair, the resistance comes from the member states. The competent authorities and the ethics committees in particular are not keen on changes to the existing legislation. The approach favored by EFGCP is to initiate public discussion nationally and with the European Parliament before the new legislative proposal is on the table, so that once the draft text emerges, the debate will be more focused and more predictable.

More than 100 clinical trials professionals from industry, CROs, academia, patient associations, the medical profession, ethics committees, and regulatory agencies convened to explore what they could usefully do to improve the prospects. Their discussions centered on optimizing the clinical trial approval system, developing a risk-based approach to clinical trial documentation, supervision, patient liability insurance, dealing with peculiarities in patient populations, and improving trial designs. As Kevin Loth of Celgene put it, "Success is dependent on a sufficient level of detail within the legislative framework." As his remarks implied, the right sort of detail was equally important.

Going into detail

Angelika Joos of MSD outlined how a single submission with a coordinated assessment procedure might make the approval process more consistent across Europe, and accelerate the conduct of clinical trials while reducing administrative burdens. Subsequent discussions ranged across issues such as how to ensure access to the right expertise, or how to deal with disagreement with the assessment among the member states. A common submission dossier might force some standardization into applications, but could result in a very long list of requirements.

Jacques Demotes of INSERM and ECRIN outlined some of the considerations in developing a risk-based approach to clinical trial rules. His tentative recommendations were for a stratified—top-down—approach through adopting a system based on risk categories, alongside a personalized—bottom-up—approach with a broad group of stakeholders generating guidelines that could be applied to individual protocols.

Participants examined some of the questions raised by this debate—including how far new legislation should drive clinical research that is considered "meaningful for society" (a concept itself open to multiple interpretations), how far rules should distinguish between trials related to authorization and trials related to comparative effectiveness, and how to keep the focus on the patient.

Detlef Niese of Novartis teased the audience with some provocative reflections on specific requirements for trials in emergency research in patients unable to consent, in research in children, and in conducting clinical trials in developing countries.

In reflecting on clinical research in children, participants pointed to the potential psychological distress over and above any medical or physiological risks that clinical trials may expose children to. They agreed there is a need to consider methodologies of trials more intensely; to avoid unnecessary pain, fear, discomfort, and risks; and to define requirements more strictly.

The discussion of developing countries noted the limited access to healthcare resources—and approved medicines—for a large proportion of the population, because of widespread economic deprivation. Deficiencies existed regarding the legal system and the protection of human rights, including, but not limited to, good clinical practice. Emphasis was placed on finding the right partner, and ensuring adequate understanding among researchers from developed countries about the legal and ethical framework and the local situation in developing countries. Involvement of civil society—patients groups and local communities—was recommended, especially for risk assessment and informed consent.

There was wide support for clinical trials in developing countries applying the same principles as in the EU, with research participants being guaranteed the same level of protection, and for demonstration of the merits of a trial for the health needs of the local population. In the same vein, the principle of benefit sharing should apply so that there is access to the product if it is proven safe and effective.

Not yet a coalition

The disparate assortment of people that assembled for this meeting cannot yet be described as a coalition—although the participants indicated by a show of hands that they are ready to explore the creation or adoption of some formal personality to maximize their impact on the upcoming debates.

Whatever the shape their lobbying exercise takes, they are going to have to shout loud and in unison to make their voices heard. They are going to have to do more than shout loud—they will have to make sure that what they are shouting is clear and simple enough for people who know nothing of clinical trials, and care even less.

They focused their discussions on what they described as "areas of particular complexity for the new clinical trials legislation"—but for nearly everyone in the outside world, any area of clinical trials is already of particular complexity.

They may not like the idea of resorting to vulgarized communications and memorable slogans, because such an approach is naturally alien to intellectually refined doctors, scientists, and industrialists. But the nature of public and political debate in Europe may make it necessary.

The discussions among the participants are still a long way from clarity of agreement or of presentation, and if they really want to intervene to influence this debate, they need to move pretty fast to get up to speed. For instance, the meeting displayed a desire for "more professionalism in ethics committees—but not professional ethics committees." Some difficulties in persuading unsympathetic audiences of the merits of such highly refined positions can well be expected.

The coming weeks will make clear whether the distinct component groups in the clinical trials community are ready to make the compromises in their own positions that will allow the confection of a message that is simple and clear enough for public debate.

One of the challenges will be to generate some enthusiasm for public discussion of a subject so remote from most people's (and most politicians') knowledge base. Since it is very hard to win (or even make) an argument on a subject that no one knows about (and therefore automatically doesn't care about), this loose coalition seeking more effective clinical trial rules is going to have to get the guardians of the public (politicians, officials, diplomats, ministers) on their side. This can be done more effectively if, even before the lobbying exercise commences, the profile of clinical trials—the positive aspects of clinical trials—is raised significantly. Only then, on that basis, is there a real chance of being able to argue a case. Without investment in such energetic efforts, the clinical trials community may remain merely unheard victims amid the hubbub of voices expressing diverse—and often contrary—views.

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