Good, Bad or Indifferent?

Unbelievably, the jury is still out. Has the 2001 European Clinical Trials Directive failed to make Europe more attractive for clinical research? Worse, is it hindering important clinical trials because it has increased the regulatory complexity, administrative burden, and related costs without improving safety of trial participants? After a decade, it is indeed remarkable that these questions should still be under intense assessment in Europe. Yet they are. Intensely and intensively.

Peter O'Donnell

That indefatigable champion of good sense in good clinical practice, the European Forum for Good Clinical Practice (EFGCP), has assiduously surveyed the beneficiaries (or victims) of the EU legislation, and has compiled a series of answers, which it has discussed at length with stakeholders and is now passing on to the European Union authorities. The key difficulties were found in clinical trial authorization procedures, ethical review, sponsorship, ensuring risk-based decision-making, and safety reporting.

After an extensive series of workshops to explore the difficulties and possible solutions, it has now passed on its recommendations to EU officials. They, in turn, are in the very early stages of what is likely to be a long revision process of the legislation.

Unresolved questions

This column will examine the EFGCP findings in detail in a subsequent issue. But it is instructive to give an indication of the sort of issues that still remain unresolved about the merits and demerits of the legislation in the nine years since it was adopted—as revealed by the areas that EFGCP saw fit to explore in its survey.

Belgium Trials

The questions still open include whether the current system of parallel reviews and approvals by all national competent authorities involved should remain for multinational clinical trials, or should be replaced by a single clinical trial authorization. And if a single authorization is to emerge, should this be obtained through a central application and central review (for instance at the EMA) or through a central application and a decentralized review—either requesting review from all authorities involved by the trial or by one authority chosen by the agency for its relevant expertise?

Should sponsors be allowed to apply to any national authority, which would act as rapporteur for a mutual recognition procedure? And should current and new procedures for authorizing multinational trials run in parallel, leaving the sponsor free to choose their favorite option?

Should a single application dossier, submitted centrally, be considered complete, with no possibility of additional national requests for documents? And—as ever in the linguistic patchwork quilt of Europe—what languages should a single dossier be submitted in? English? Or national languages?

The ranking of which areas need clearer definitions varies from stakeholder to stakeholder—so EFGCP has tried to establish the good, the bad, and the ugly among the current definitions for sponsor, investigational medicinal product, substantial amendment, and noninterventional study.

It also assessed views on whether the current definition of a single sponsor for a trial should remain, or whether there should also be options for cosponsorship, with the coordinating sponsor retaining legal and penal responsibility, or for joint sponsorship, sharing legal and penal responsibility but with a single protocol, single trial identification number, and single database.

The survey sought views on whether there should be the same liability insurance conditions for trial participants in all EU countries, and whether it should be covered by the national health care system or a common fund (such as industry-run) rather than by an insurance company.

Opinions were canvassed on whether multinational trials should be supported by funding mechanisms at a European level (such as through a European version of the U.S. National Institutes of Health), and whether public–private collaboration should be promoted by clearly defining rights, obligations, and responsibilities of the co-sponsorship partners at a European level.

Ethical review

Areas of enquiry also extended to the desirability (or otherwise) of a more harmonized ethical review process in the EU, of raising the quality of ethical review, and of harmonizing it through accreditation and training of ethics committees. Views were gathered on whether a single ethics review opinion should remain for each EU member state, or whether this should apply only to single-center and national multicenter trials, with a single Europe-wide opinion for multi-national trials. The questionnaire also probed responders on where greater clarity was needed in what should be dealt with by ethics committees and which by national competent authorities.

Should there be only one single expedited entry of suspected unexpected serious adverse reaction reports into the EU's central EudraVigilance database, or should the information be transmitted more widely to authorities, sponsors, and ethics committees? And should the current "one-size-fits-all" approach of the legislation be replaced by a risk-based approach?

Overall, EFGCP asked respondents to indicate whether they agreed that urgent action was needed to revise the system. All of this raises other interesting questions. If the legislation is not fit for purpose, why is it taking so long to pull together any consensus on the need for change? Does this tell us more about the slowness of the EU legislative system, or about the patience—not to say passivity—of the European clinical trials community?

Gallant little Belgium

Meanwhile, some of the EU countries are fighting back against the risk of losing clinical trials business—risks that arise in part from the regulatory constraints in the European directive now under so much fire, and in part from changes in the broader commercial and scientific context.

Belgium took advantage of "international clinical trials day" on May 20 (which is just as well, because this columnist would not have known such a day even existed) to issue a warning call that its leadership as a trial center was under threat. "The shift of trials towards emerging countries could change the situation and have grave consequences on the knowledge economy, research and development, and on companies in our country," said a coalition of industrialists, physicians, and the clinical trial community.

Claiming a top position in trials (with 9% of European trials conducted in Belgium), it vaunted its "dense and dynamic" network of scientists, hospitals, industry, and innovators as the perfect setting for early-stage trials. But, it cautioned, lower costs in India and China are luring large-scale trials, and even Eastern Europe is tripling its grip on the market.

This is the background to the "Initiative to Promote Clinical Trials in Belgium," which brings together doctors, patient associations, and hospitals to tell prospective subjects about trials, and encourage them to take part. That way, it says, they can get earlier treatment and play a vital role in society. "Clinical trials not only help health; they also boost the knowledge economy and employment in our country."

To boost the country's attractions, Belgium is promoting electronic submission of applications, rapid trial authorization, simplified administration, cheaper procedures, trained staff, and more efficient subject enrollment.

Indefatigable administrators

Also fresh off the agency design table is a concept paper on upgrading guidance on clinical investigation of medicinal products for the treatment of cardiac failure. It says that emerging data from recent clinical trials have shown the determinant role of the patient clinical profile at presentation on the outcome of the studies, in particular the key role of systolic blood pressure and renal function. A more selected enrollment of patients should therefore be examined, it concludes.

To better detect an improvement of clinical symptoms or demonstrate a clinical benefit, new composite trial end-points have emerged that are particularly challenging for regulatory decisions. More clarity is needed on the applicability of these composite end-points for regulatory purposes. Commendably, the document notes that "It is not totally clear whether at present unequivocally feasible and scientifically sound proposals can be made to address the major problems identified. Consequently, prior to drafting revised regulatory recommendations it seems prudent to initiate discussion with experts from academia to exchange views..."

If only the EU had done that with the Clinical Trials Directive.

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