Peter O'Donnell
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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.
Conflicting views
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.
