Clinical Trials Directive Hammered at EMEA Meeting in London

October 3, London-A major meeting hosted in London by the European Medicines Agency provided plenty of examples from industry and academia of what doesn't work in this 2001 legislation (Directive 2001/20/EC). Even Thomas Lnngren, the Agency's executive director, acknowledged that there are problems in the implementation of the directive, and that there was "a need to find a way forward." But the contributions that European Union officials made to the debate fell a long way short of offering any dramatic improvements in the foreseeable future.

The catalogue of problems was extensive. For Alan Morrison, vice president international regulatory and safety at Amgen, the legislation needed changing, at the European and national level. There was "an urgent need to address fundamental issues" on loose definitions (particularly of what constituted "substantial" and "nonsubstantial" amendments to a trial), divergent information requirements for trial authorization applications, divergent national rules on manufacturing and labelling of investigational products, and inconsistencies in review processes both at the regulatory and ethics committee level. He pointed out that some member states impose "unreasonable" requirements going beyond the directive-such as refusal by some of them to accept the qualified person's declaration as an assurance of GMP compliance for third-country manufacturers.

Mats Ericson of Wyeth Research insisted that improvements to clinical trial authorizations had to be achieved. This would require renewed commitment from all national authorities to implementing the directive so that it resulted in harmonization. National exceptions from EU guidelines would have to be removed, agreed EU guidelines would have to be respected, and no further national guidelines should be issued. It would also need a clearer focus on public health issues-notably safety reporting.

The current duplicative assessments are not the best use of EU resources, said Ericson. Above all, what is needed is a new, additional and optional alternative procedure. This should provide one assessment and a single approval per study-particularly valuable for multinational studies. He recognized that this would require some tough decisions about which body would become responsible for the scientific review (and how it was resourced and funded), and how its "approvals" would be transposed across all member states involved in a trial. Eventually, it might even require a tough decision to switch to a single EC review, he suggested. But it was necessary to consider radical change, because there was "a fundamental flaw in the Directive which cannot be addressed within the current framework," he insisted.

For Gaby Danan of Sanofi-Aventis, safety reporting was bedevilled by divergent behaviour from country to country. He listed variations between national rules on reporting SUSARs (in relation to whether they originated locally, within the EU or beyond), on investigational products, on trials, on indications, and on unblinding rules. He said national practice varied on annual safety reports, with some countries demanding serious adverse reaction reports periodically, others cumulatively, some local and some global, some by trial and some inclusive, some blinded and some unblinded.

Similarly, practice in electronic transmission of case safety reports to EudraVigilance resulted sometimes in high duplication rates, and sometimes no report at all, while data quality varied widely (sometimes with no narrative or containing inconsistencies), and occasionally failed even to identify the investigational product. The variations were wide too in national requirements for transmitting information to ethics committees and investigators-whether to supply all or just local SUSARs (and whether on paper or in electronic format), whether to supply line listings or just a fraction with specific data, whether to supply expedited or periodic safety information, and whether to include SUSARs from approved trials only or from any other trials involving the investigational product.

The criticisms from academia were even more virulent. Rory Collins, BHF Professor of Medicine & Epidemiology at the Clinical Trial Service Unit at the University of Oxford, argued that the proliferation of laws and guidelines may make clinical research less reliable, and so harm patients, rather than help them. He claimed that the entire EU approach was misconceived, with an obsessive attention to procedural detail obscuring the real purpose of clinical trials.

His central thesis was that moderate effects of treatments can have large effects on public health, and reliable assessment of moderate effects on mortality and major morbidity requires large randomized trials. "Consequently, bureaucratic obstacles to large randomized trials may well inadvertently reduce public safety," he said. The directive-and its associated good clinical practice requirements-was making large trials increasingly difficult, maintained Collins: They had doubled the costs of running noncommercial cancer trials in the UK, and had added 6 to 12 month delays to starting; and they introduced uncertainties over interpretation, and increased demands for documentation. "Clinical trial units are unable or unwilling to start trials in non-UK centers due to different interpretations in different European countries," he said.

His concerns were echoed by Silvio Garattini of the Istituto Mario Negri. Increased red tape and bureaucratic requirements have doubled or quadrupled the cost of trials, and made approval of multicenter international trials more complicated. The result has been a drop in the number of independent trials, he said.

Monique Podoor, Director of the Data Centre at the European Organisation for Research into Treatments for Cancer, also complained that inefficient harmonization at member state level and disharmony at regulatory and ethics committee levels across the EU was making multinational trials more complex and increasing the administrative workload and the costs. Like many participants from academia, Podoor also highlighted the particular difficulties the directive presented for noncommercial research-because it covered only drug treatments, and imposed requirements that were excessive or irrelevant on reporting and on sponsorship.

For Stefan Bielack, a leading pediatric oncologist from Stuttgart, the directive has meant "too much paper," with safety reporting "unbelievably and unnecessarily complex for multinational trials." For expedited reports in particular, there is "too much garbage to too many recipients."

GCP inspectors too have problems with the current situation, according to Pierre Henri Bertoye of the French regulatory agency, Afssaps. Despite the directive, there is an unmet need for a harmonized reference for GCPs as an EU standard, he said-for investigators, for ethics committees, and for inspectors themselves.

Speaking for the European Network of Research Ethics Committees, Michael Fuchs from Bonn University said the directive has not changed the status quo as far as membership of ethics committees is concerned, and has allowed the continuation of differing national structures. But many of them are suffering from an increased bureaucratic burden and the complicated legal situation created by the directive-as well as, in many countries, funding difficulties.

Recommendations made during the meeting included provision of pan-European training for assessors, so as to promote consistency of approach, and a single clinical trial authorization for the whole of Europe based on mutual recognition of harmonized requirements, and with a single submission point. There was much talk of a single ethics committee opinion per member state, with clarification of the responsibilities of central and local ethics committees, a common application form for ethics committees, and parallel review of applications by the competent authority and ethics committees. There was wide support for a strengthened role of the Clinical Trials Facilitation Group operated by the Heads of Medicines Agencies in Europe. This, it was repeatedly urged, could play a key role in coordination-and arbitration-of the review process, and in providing an appeal mechanism for sponsors.

Other issues raised included academics' desires to see the scope of the directive widened to cover all clinical research, contract research organisations' concerns over the liability of the legal representative, patient representatives' concerns over transparency of trial information and informed consent of subjects, and ethics committees' aspirations for funding and training.

Hartmut Krafft of the Paul-Ehrlich Institute in Germany, representing the Clinical Trials Facilitation Group (CTFG), suggested that many of the problems identified could be solved without any change to legislation. In his view it would be enough simply to ensure greater coordination-either among member state authorities, or with more presubmission contact between sponsors and national authorities, using a voluntary harmonized clinical trial application. "At present, CTFG sees no need for a new legal framework," he said.

Similarly, Brian Davis of the UK's Medicines and Healthcare products Regulatory Agency, and another key figure in the CTFG, acknowledged gaps in the current system, but dismissed the need for major legislative changes. He conceded that there were imprecisions in definitions and divergences in national practice, and that EudraCT information is "not up to date" and Eudravigilance data "can't be analyzed." But he believed it was possible to remedy these problems within the present legal framework, with the need only for a new mandate for electronic SUSAR reports, and modified requirements relating to ethics committees.

Georgette Lalis, the European Commission director with specific responsibility for pharmaceuticals, acknowledged that there are problems with the directive, but said it had brought improvements to the quality of clinical research and the protection of patients. There would be no dramatic solutions to the issues raised, she stated. The Commission would reflect carefully on the views expressed, and would consult widely on possible remedies to the deficiencies identified. But she made it clear that most of the focus would be on achieving better coordination among national authorities within the existing legal framework.