More Trouble Over EU Clinical Trials Rules

January 1, 2003

Applied Clinical Trials

Applied Clinical Trials, Applied Clinical Trials-01-01-2003,

European organizations express their concerns over the implications of the EU guidances issued in response to the 2001 directive.

Right up to the end of last year, leading figures in the European clinical trials community were voicing serious criticisms of the way that the European Unions 2001 directive is being implemented at the national level. The anxieties they were experiencing during 2002 about European clinical trials rules clearly will not be dispelled for quite some time in 2003, either.

EORTC director-general weighs in
A lack of harmony in European clinical trial regulations is hurting patients, warned no lesser figure than Professor Franoise Meunier, director-general of the European Organisation for Research and Treatment of Cancer (EORTC), as this issue of Applied Clinical Trials went to press. EU countries must harmonize their rules, she insisted when she spoke at a symposium on molecular targets and cancer therapeutics in Frankfurt, Germany, at the end of November.

Hamstrung by red tape Meunier claims that international clinical trials within Europe are being hamstrung by red tape and disparate legal regulations in different countries. The lack of harmonization is jeopardizing progress in establishing state-of-the-art treatment strategies, denying patients the benefits of advances, and hampering Europes ability to compete with countries outside Europe, she insisted. The situationwhich the EU clinical trials rules were intended to resolveleads to pitfalls without improving patients safety or the quality of science and cancer care, she said.

Claiming to represent concerns felt by European oncologists and research scientists, Meunier went on to spell out that although the EUs 2001 directive was a step toward promoting the conduct of clinical trials and facilitating clinical research, it risked failing to establish the appropriate legal and regulatory framework to avoid duplication of research and cut the time needed to establish state-of-the-art treatments.

Key topics left open. Professor Meunier said that the directive leaves too many key topics open to interpretation by national authorities. These included ethical approval and protocol amendment procedures, regulations for reporting serious adverse events, informed consent documentation, requirements for drug labeling, costs of nonsponsored trials, translational research issues such as exchange of tumor materials and tissue research, and insurance requirements by ethics committees.

As a consequence, she said, We see too many drifts in documents drawn up by nonmedically qualified people who tend to adapt sometimes conflicting directives and national requirements. Subjects should be offered the chance to join a clinical trial with comprehensive yet pragmatic and understandable information, and countries need to have clear rules and regulations in common if research is not to be seriously hampered by bureaucracy and misinformation, said Meunier.

Despite the original goal of the directive to facilitate clinical research in Europe, the regulatory hurdles and approval process may persist. It remains to be seen whether the directive will actually decrease the high level of complexity faced by investigators and promoters of research, she said.

EFGCP makes its case
The European Forum for Good Clinical Practice (EFGCP) has also continued to marshal its arguments. In a new position paper on the EUs draft GCP implementing texts, it warns that certain requirements the EU and its member states are imposing are excessive and may actually reduce the number of clinical trials placed in the European Union.

The EFGCP is not entirely negative in its approach. It says that:
overall, the set of implementing texts proposed represents a considerable contribution to GCP in the European Union, and through the EU, to countries influenced by EU legislation, which will be able to borrow regulatory texts of high quality. It could turn the EU into a more homogenous regulatory zone for conducting high-quality clinical trials. It fills the regulatory deficit which the EU has had for many years compared to the USA, and thus adds credibility to the outstanding clinical work produced in general in the EU. And it offers the European volunteer and patient participating in clinical trials one of the best protections in the world.

Voluminous documentation. But the EFGCP complaints are very specific. The documentation required in the EU for starting a clinical trial will be the most voluminous in the world, it says, adding that this is in part because redundant information is required.

Sponsors will have to generate new regulatory documents, the EFGCP points out: the investigational medicinal product dossier (IMPD), a form for each ethics committee, and a form for each member state. But most information to be submitted in the application forms for approval from ethics committees and authorities is redundant, and already available in the protocol and the investigators brochure. The protocol contains a synopsis, and yet summaries of the protocol are required. And a full IMPD will contain much more information than an investigators brochure, so the shorter timelines that the new EU rules envisage for ethics review will be undone by the longer preparatory work for sponsors upstream.

Regrettably, says the EFGCP, information which is already in the hands of the member states will need to be provided by the sponsorincluding the summary of product characteristics of a reference product, all information about reference products, and the decision authorities have granted.

Not only are sponsors going to be required to provide redundant information, they will also have to provide irrelevant information, says the EFGCP. The information required about the number of subjects to be enrolled at each site and the sex ratio is notoriously difficult and so imprecise that the data is already obsolete and irrelevant when the first subject enters the study.

A string of criticisms. The EFGCP also lists a string of other equally specific criticisms of the draft texts. The system proposed does not sufficiently protect the sponsors intellectual property, because the possibility of violating confidentiality is very high, with duly appointed experts from member states having access to the proposed European clinical trial database. It introduces risks of delays and inconsistent pan-European study conduct by requiring new authorizations for amendments to studies. More information sharing is imposed on the sponsor, with continuous updating of project management information and greater circulation of safety information. And new, near-impossible responsibilities are imposed on the sponsor, with an obligation to make a declaration that the clinical trial will be performed in accordance with GCP.

Conference report. This column has already mentioned some of the European concerns emerging in this area (see Applied Clinical Trials, October 2002). It offered some highlights from an EFGCP conference in September on the subject. Since then, the EFGCP has formalized its conference conclusions, which include some tough talking. In its conference report, it says:
The imposition of administrative and bureaucratic hurdles that impede the realisation of these core values will undermine European health research and healthcare. It is critical that all of the implementing texts are streamlined, systematically related to one another, procedurally and terminologically related to one another, and firmly in agreement with todays international standards for ethics and GCP.

That September conference allowed the EFGCP to articulate a finely tuned expression of optimistic expectation over how the EU texts should be framed. The report ran:
Expediency and clarity can be achieved in the practical framework created by the implementing texts if internationally developed and recognised standards, to which the EU institutions contributed, are referenced and not altered in their interpretation without demonstrable reason. In particular, the Declaration of Helsinki and the International Conference on Harmonization guidance texts provide fundamental references and commitments for the vast majority of EU sponsors and researchers involved in the development of medicines. Altering or undermining these commitments without clearly stated reasons will result in conflict, confusion, and inconsistency in applying ethical and scientific principles to European health research, threatening the integrity of protections for human subjects. The EFGCP and the participants in the Forum Discussion considered that no contradiction need exist between these commitments, the Directive, and the achievement of this expediency and clarity in the final implementing texts.

EFGCP intensifies its criticisms. No changes were made to the EU texts to satisfy the EFGCPs elegantly phrased aspirations. So now that organization has written to the senior EU officials most closely involved in the legislationErkki Liikanen (European Commissioner for Enterprise and Information Society), Philippe Busquin (European Commissioner for Science, Research and Development), and David Byrne (European Commissioner for Health and Consumer Protection).

EFGCP has not minced words this time, making clear that it has serious concerns regarding the potential addition of cumulative hurdles to research that provide neither clear add-on ethical or scientific value, nor demonstrated benefit to the patient or the public. The opposite sometimes appeared to be the case, says the EFGCP. And in straightforward language hardly habitual in the normally placid world of clinical trials in Europe, that group hammers its points home without ambiguity. It says the draft implementing texts:
will have a dramatic and prohibitive effect on the prospect for European research needed to address todays, as well as future, health challenges for the European citizen. Should the texts be adopted in a form similar to what is being proposed, serious and unnecessary impediments will arise.

High stakes. At risk are the development of orphan medicines, cooperative research within the EU and beyond, and the international competitiveness of the entire European pharmaceutical industry. The EFGCP suggests that the stakes are high enough to put into question the future of all health research in Europe.

The original EU intention was to create a research environment in Europe in the interest of improved public healththis will be seriously curtailed if the Commissions responsibilities for producing guidance documents do not achieve an adequate European framework, says the EFGCPwhich claims to represent the point of view of leading stakeholders in European health research from the public and private sectors, members of competent authorities, ethics committee representatives, hospitals, patients, researchers, and others.

Debate continues
The deadline for EU member states to bring in their national rules is May 2003, and the new system is due to start functioning fully in May 2004. The debate is likely, therefore, to be echoing across Brussels for many months yet.

References
1. Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use. Official Journal L121, 3444. (1 May 2001, also available at pharmacos.eudra.org/F2/eudralex/vol-1/new_v1/dir2001-20_en.pdf).

SIDEBAR: Background to the clinical trials conflict
The European Union is proposing a number of implementing texts, providing detailed guidance on specific areas of GCP under the 2001 Directive. The implementing texts are intended to guide EU member states in creating their own national legislation to put the EU rules into effect.

Usual system. The usual EU system leaves detailed implementation of EU rules to national legislative systems; however, if too much flexibility or margin for maneuver is left to the member states, the initial harmonizing objective of an EU rule may be frustrated. That is the principal complaint of the European clinical trials communitya fragmented EU context for clinical trials has been only marginally improved by the 2001 directive, and what little improvement it brought is likely to be vitiated by discordant national implementation.

Detailed issues. The texts cover detailed issues such as a European database of suspected, unexpected serious adverse reactions; application formats and documentation for clinical trial authorizations from the authorities; for ethics committee opinionscollection, verification, and presentation of adverse reaction reports arising from clinical trials; good manufacturing practice for medicines used in clinical trials; import of investigational products; trial master file and archiving; and qualifications of inspectors of clinical trials. The latest published drafts of the implementing texts may be seen at pharmacos.eudra.org/F2/pharmacos/dir200120ec.htm.

Numbers. About 50006000 clinical trials are set up in the EU every year by the pharmaceutical industry, and 50006000 more clinical trials are set up by other sponsors (physicians, academia, nongovernmental organizations, and public health authorities). In the industry-sponsored sector, about 500,000 subjects and healthy volunteers are enrolled in the EU each year.

Costs. The cost of these clinical trials is estimated at E5 billion per year, including grants to investigators, salaries, and operating costs of clinical research departments in the pharmaceutical industry and contract research organizations, costs of analytical and clinical laboratories, drug packaging facilities, courier companies, telecommunications, transportation, ethics committees, printers, and so on.

The European clinical trials community estimates that the problems introduced by these draft texts could increase the cost of clinical trials by 30%.

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