It's Official: CT Directive Poses Problems

A 76-page official report has just been published on the jumbo European Union clinical trials regulation conference that took place in London on October 3. It confirms—if only timidly—what many have been saying unofficially for ages. The EU rules on clinical trials don't work properly.

Peter O'Donnell

Avid followers of the subject may recall that Applied Clinical Trial's own—somewhat shorter—report of the meeting appeared on the magazine's Web site within days of the October meeting, under the title "Clinical Trials Directive Hammered at EMEA Meeting in London" [actmagazine.com/appliedclinicaltrials/article/articleDetail.jsp?id=463968&searchString=october%203]. The joint sponsors of the meeting, the European Medicines Agency and the European Commission, have delivered a weightier but rather more optimistic account of what went on [www.emea.europa.eu/pdfs/conferenceflyers/clinicaltrials/report.pdf].

Their summary records general recognition among conference participants of the merits of the EU legislation—a common legal framework, a legal basis for compliance with good clinical practice, and improved protection of individuals through ethical approval procedures for clinical trials. "The conference generated a very useful dialogue," it concludes.

It does acknowledge that "in some cases, problems have been encountered." But it suggests that much of the difficulty arises from what it sees as nothing more serious than "different interpretations and different implementation in the national legislation of the member states," and that "additional clarification, guidance, and harmonization" could provide a sufficient remedy. Only then does it note the feeling among conference participants that solutions to "some of the difficulties experienced" will nevertheless need legislative changes.

"Any change to the legislation is likely to take some time," the report goes on, so it backs the meeting's support for an immediate start to work on issues that can be resolved without such a change—notably multinational clinical trials, safety reporting and monitoring, noncommercial sponsorships/trials, CTA dossier and process, and IMP-related issues. "Other areas that will require specific attention include increased transparency and availability of information on clinical trials, and the application of ethical principles and GCP standards in developing countries," it adds.

New suggestions

Any hopes that this meeting would reduce rather than widen the scope for discussion have also been quickly dashed by the immediate follow-up. The organizers invited further comment for a limited period after the meeting—and they certainly got it! A further 27 pages of observations and suggestions from more than a dozen participants who felt they didn't quite get their point across during the meeting itself appear on the EMEA website [www.emea.europa.eu/pdfs/conferenceflyers/clinicaltrials/postconfcomments.pdf]. They include concerns from industry, regulators, and academia. Shayesteh Fuerst-Ladani of Kuros Biosurgery AG in Germany raises the frequent dilemma of companies that have incorporated EMEA advice into their trial design and then find national competent authorities questioning the design and requesting changes. "Would it be possible to have a link?" he asks plaintively, and not unreasonably, between EMEA scientific advice and the assessment of national authorities.

Valiantly defending the noncommercial sector, Dr. David Baldwin of the European College of Neuropsychopharmacology urges a rethink of trial classification. "If studies are unlikely directly to change clinical practice, they should not be classified as clinical trials, and the onus should not be that studies are clinical trials until proved otherwise, but rather the other way round," he says. Instead, "what is needed is a new class of study—'a small clinical trial' with maybe under 100 participants, which could be dealt with as an experimental medicine protocol." Without this change, he argues, the EU rules "will strangle research innovation in Europe, to the great advantage of our competitors in other continents."

The question of insurance again reared its head in this post-meeting discussion. Ólöf Yrr Atladóttir of the National Bioethics Committee of Iceland says that in her country: "We are experiencing an ambiguous and problematic situation concerning insurance for participants in clinical drug trials." She wants to know how far insurance requirements might be coordinated within the member states, perhaps with agreement on "some base line." Her anxieties are shared by Professor Janet Darbyshire of the UK Medical Research Council's Clinical Trials Unit. In her view, "putting in place suitable arrangements for insurance and indemnity in other European member states is both complex and costly and requirements vary." She said multinational noncommercial clinical trials in Europe would be greatly facilitated if the EU "were able to support the development of a harmonized approach that provided adequate protection to patients without undue financial burdens for sponsors."

Uncertainties persist among national authorities on other areas too. Professor Gunnar Alvan of the Swedish Medical Products Agency asks whether it is not "time to clarify the procedure for clinical trials approvals" by defining and distinguishing more precisely the respective responsibilities of national competent authorities and the European Union.

With characteristic bravura, Francis Crawley of the Good Clinical Practice Alliance–Europe and Applied Clinical Trials Editorial Advisory Board member has posed two questions to the organizers: In light of the meeting, do they believe that the EU legislation "is a major contributor or detractor to public health in Europe," and whether it helps or hinders "making Europe competitive in the global market place of clinical trials?" He also slices through much of the debate with the suggestion that "all distinctions between commercial and noncommercial/academic clinical trials should be eliminated" from the legislation. "Sources and nature of funding are not good clinical practice considerations," he points out.

And in a direct challenge to the tone of the official report, Professor Kathy Pritchard-Jones of the International Society of Paediatric Oncology says: "We were very concerned to see that the presentations from the representatives of the Clinical Trials Facilitation Group thought that the EU Clinical Trials Directive was basically sound and that only some 'fine-tuning' was necessary."

Industry concerns too

An official pharmaceutical industry view—although provided for a different purpose—makes the same trenchant point. "The Clinical Trials Directive has failed to achieve its stated goal of 'simplifying and harmonising the administrative provisions governing clinical trials' as well as creating a simplified and competitive environment for clinical trials in the EU," according to a submission from the European Federation of Pharmaceutical Industries and Associations (EFPIA) to a broader and separate EU debate on the future of pharmaceuticals. "The main problem," says EFPIA, "is that member states have adopted different approaches in implementing the clinical trials directive, so the benefit of a single approach has been watered down." It calls for "more coordination," more "agreement on definitions" and fewer "country-specific requirements which go beyond the directive." In addition, says the industry association, more radical action will also be needed. This should take the form of a new and optional alternative procedure for multicenter trials to cater for applications, approvals, and supervision, and that would provide a single approval, "since there are some fundamental weaknesses of the clinical trials directive that cannot be remedied via further consensus building."

Waivers for pediatric trials

The November meeting of the EU's pediatric committee took one small step toward greater clarity on where clinical trials will be required—and where they won't be—under the EU's new rules for stimulating the development of medicines for children. The principle of these new rules is that every application for authorization for a medicine has to be accompanied by a plan for pediatric trials: a pediatric investigation plan.

The committee is acting to remove the obvious anomaly of requiring pediatric trials for medicines with no role in the treatment of children. It is recommending class waivers for conditions that do not affect children, including 17 symptomatic conditions relating to different types of cancer, neurodegenerative conditions, and other conditions that occur only in adults.

The list, which will be regularly updated, refers to waivers only for the treatment of these conditions; it does not offer waivers for medicines used for their prevention or diagnosis. Companies are, however, also entitled to seek waivers for individual products. At its November meeting, the committee adopted a product-specific waiver for lasofoxifene tartrate, from Pfizer, in the area of bone diseases. This frees the applicant from the requirement to conduct trials to develop this medicinal product in the pediatric population. It is the fourth product-specific waiver issued since the system came into operation. The committee is also putting in place its procedures for the assessment of pediatric investigation plans—which will remain an obligation for most authorization applications—or of requests for waivers. See page 24 for more on this topic.

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