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Contradicting decisions call for a unified clinical trial authorization process.
Nearly a decade after the European Union introduced its new clinical trials rules, the system is still stifling rather than stimulating research and innovation, claim many of its critics. But the EU authorities remain hesitant about changing the rules, and until now the clinical research community has remained split over what changes to demand. A workshop in Brussels in July marked the first step in overcoming those divisions, with a concerted attempt to begin drawing up a roadmap for clinical research in Europe.
The initiative focused on defining the ideal clinical trial authorization (CTA) procedure. Over recent months in Europe, there has been a growing consciousness of the need for a single CTA process that would provide clear definitions of the respective roles of the competent authority (such as in assessment of the investigational product at the EU level) and the ethics committees (such as protection of participants at the national level). The search is now on for greater efficiency that will not increase the risk for trial participants.
Hartmut Krafft, chair of the clinical trials facilitation group operated by the heads of the European Medicines Agencies (whose day job is head of the Clinical Trials Unit at the Paul-Ehrlich Institute in Germany), admitted that divergent decisions emerged from competent authorities and ethics committees in Europe. Between May 2004 and June 2008, there were 155 cases where the regulatory authorities approved an application but the ethics committees' opinions were unfavorable, and 89 where the ethics committee gave a favorable opinion but the regulatory authority turned the application down.
Martyn Ward, Head of the Clinical Trials Unit at the UK's MHRA, conceded that despite the merits of the clinical trials directive, complications had crept into the implementation. A lack of EU guidance had led to local interpretation (and differential timing) when implementing the directive in national legislation, and this had been particularly aggravated by EU enlargement, which had subsequently brought 12 new member states into the picture, with varying experience, resources, and priorities in terms of clinical research.
As a result, the information to be provided in CTA applications needed clarifying and harmonizing, timelines needed to be more explicit, and there was scope for aligning CTA assessment outcomes in different member states. But in Ward's view, the existing mechanisms were largely sufficient to make the necessary improvements. The current legislation, he said, is intrinsically sound, and a lot can be done without radical change.
His judgement was not universally shared. Speaking from the viewpoint of a commercial sponsor, Angelika Joos, Director of Regulatory Policy Europe at Merck Sharp & Dohme, pinpointed the ambiguities in safety reporting requirements and in definitions of investigational products or amendments that arose from divergent national implementation. The consequences of this fragmented and complex regulatory environment, says Joos, include a multiplicity of assessments with divergent outcomes and increased administrative burdens, necessitating additional staff for the application and submission process and safety reporting. Companies are obliged to cope with multiple scientific discussion partners with a different focus, the rediscussion of issues at different levels, constant transfer of product and regulatory histories, complex feedback mechanisms, and specific national amendments to global study protocols.
A still more assertive view came from Mats Ericson of Amgen, speaking on behalf of the European Federation of Pharmaceutical Industries and Associations. He highlighted the complexity of managing large multicenter multinational trials when they are reviewed and supervised separately by each country (and, he pointed out, 60% of all trials are conducted in more than one member state).
"The issue of divergent interpretations cannot be fully resolved by modifications to the directive," he insisted. That would not be enough to resolve distinct national requirements on CTAs and on good manufacturing practice, or the conflicting review outcomes and requests for changes, or the differing approaches to amendments. It is, he said, "time for a change."
EFPIA wants to see an optional, centralized, approval process enforced through a new regulation that would generate EU-wide CTAs, based on assessments by the best expertise across Europe. This would be a more efficient use of European resources, and would even be attractive internationally, he said.
Jane Apperley of Imperial College in London noted the additional problems identified in noncommercial trials of increased time to approval, increased costs—including for insurance, and difficulties finding sponsors for multinational trials. And among the requests from another spokesperson for the noncommercial community, Anastassia Negrouk, Head of the Regulatory Affairs and Intergroup Unit at EORTC, included a call for greater flexibility on the language to be used.
All member states should be prepared to accept an application in English, Negrouk said. And greater involvement of patient representatives in ethics committee discussions was urged by Jan Geissler of the European Cancer Patients Coalition. Only in Austria, France, and the Netherlands are patient advocates explicitly mentioned as committee members, said Geissler.
This was the first in a series of five planned workshops over coming months with the aim of offering Europe's regulatory authorities, at a final conference next April, a unified position on how the EU clinical trials rules should be crafted—a component that the organizers say was missing during the original development of the directive. Watch this space.
The echos of the European Union's inquiry into competition in the pharmaceutical industry are still rippling across the continent—and even into the United States. The clinical trials community may not be hugely concerned over the intricacies of the balance between anti-trust law and intellectual property law that the final ruling—published on July 8—tries to strike. But everyone involved in the development of medicines in Europe will have read with interest the passage about the EU's determination to promote innovation.
The European Commission, says the final ruling, "is committed to the development of an EU pharmaceutical framework for the 21st century which promotes innovation, in particular in areas with unmet medical needs." The ruling notes that the Commission "will adopt a report on the use of personalized medicines and '-omics' technologies in pharmaceutical research and development and on the possible need for new Community instruments to support them, by 2010." This report will, the Commission forecasts, provide an opportunity to consider the current data exclusivity system, and its ability to contribute to innovation and improve access to medicines.
After 18 months studying the sector during its inquiry, the Commission now feels able to say with confidence that "with the emergence of new technologies like pharmacogenomics and patient-specific modeling and disease simulators, personalized medicine is now on the horizon. In the long term, doctors may be able to use genetic information to determine the right medicines at the right dose and time. This field is already affecting companies' business strategies, the design of clinical trials, and the way medicines are prescribed. Although it is too early to say whether '-omics' technologies will indeed revolutionize the sector, the Commission closely monitors the area and will reflect on how it can support its development."
The Commission also goes on the record in its ruling as fully supportive of "further international harmonization in the area of marketing authorization, mostly between Europe and the United States, "as this has the potential to considerably reduce the costs of market access and innovation by reducing unnecessary regulatory divergences."
According to the European Forum for Good Clinical Practice, the current EU rules require a CTA by a competent authority and a favorable opinion from a lead or central research ethics committee as a prerequisite for the performance of a clinical trial. In multinational clinical trials this authorization process has to be followed in each country where the clinical trial is to be performed. The content of the CTA application dossier is defined by each member state in a different way, and the review processes impose different additional requirements, which result in a longer trial preparation period for multinational trials and increased administrative cost. The answer would be a single CTA, irrespective of the number of participating countries, either by the development of a single CTA application across Europe or the mutual recognition of authorizations by national authorities, with a better definition of the roles of ethics committees and competent authorities in the process.
Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.