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Clinical researchers strive to meet ongoing challenges posed by the EU Directive.
ASnybody who thought GCP would simply become a reality in the European Union on 1 May 2004—the date when the EU Clinical Trial Directive 2001/20/EC became effective—was sorely mistaken. Implementation and compliance continue to cause difficulties.
In Brussels, panelists and speakers tackled the thorny issues surrounding the EU Directive.
Because the directive is not a regulation, it requires transposition into national law. National variations seem likely to persist, and national laws often prevail, even when they are in conflict with the EU Directive. The harmonizers' vision has not yet materialized.
"The directive is good, but it is a work-in-progress and it needs to be monitored," Michael Griffith, chief executive of Fighting Blindness Ireland, told delegates at May's meeting of European Forum for Good Clinical Practice (EFGCP) in Brussels. "The biggest problem is lack of information. We need details on how the directive is being implemented in each country, and we need information on specific difficulties in each country."
The consultation process was very poor, and the views of academic researchers were not sought, he said. He attributed this largely to the fact that the directive comes from the Directorate-General (DG) for Enterprise, rather than the DG Research or DG Health units.
Griffith identified three common difficulties:
Close scrutiny of the situation across the European Union is required to ensure that any problems are immediately dealt with and no undue delays occur, and the European Commission (EC) must introduce a monitoring system and ensure good communication, he noted. To ensure patient groups, national regulators, academics, and the public are made aware of developments, an annual conference should be organized, either directly by the EC or by the EFGCP and European Platform for Patients' Organisations.
"Morale and enthusiasm for research are waning," commented Maxine Stead, assistant director of the U.K. Clinical Research Network Coordinating Centre. "There is a need to address the problems and provide solutions quickly to maintain interest in research."
Industry representatives also appear far from happy about the directive. New member states sometimes have unrealistic expectations, leading to trials going elsewhere and undermining the ICH (International Conference on Harmonization) process, according to Dr. Beat Widler, global head of clinical quality assurance at Hoffmann-La Roche. Moreover, regulatory variations between countries are interfering with proper study conduct.
"Some states are keeping local requirements and adding EU requirements. This causes delays in starting trials and increases costs. Also, a breach of confidentiality may occur when extensive documentation is submitted to ethics committees," he told EFGCP attendees.
There are gaps in clarity and consistency, and gaps in implementation, Widler continued. Requirements may change during the transitional phase. Certain countries have demanded that ongoing trials should comply with the directive, while others have not, and this means the same study is conducted according to different rules. Such problems look set to persist for some years. Also, supporting guidelines and guidance documents are still not universally available, and there is a lack of transparency about how documents get prepared.
On the plus side, EudraCT works and was almost delivered on time, but overall there is insufficient harmonization, he remarked. Local forms are still being used, as well as EU-agreed ones, necessitating translation of documents. German regulators, for example, request full viral safety testing in early trials, while others do not. The definition of an investigational medicinal product varies widely, and Spanish regulators are applying a very broad definition. Certification of third party comparator products is often impossible, and EU member states do not have a common view on how to apply Mutual Recognition Arrangements, or MRAs.
"The SUSAR process dumps investigators and ethics committees with loads of unhelpful, relatively unfiltered, and uninterpreted information, resulting in no improvements in transparency or patient safety," said Widler. "Inspection manuals are not publicly available, and inspection findings seem to depend on the subjective opinion of inspectors."
He listed four unanswered questions for the EU regulators: What is the EU position on risk management? Are the European Medicines Evaluation Agency (EMEA) and EU to be aligned with FDA on this approach? Were key performance indicators defined, and are they being tracked? For Phase I, can umbrella protocols become an option to speed up the process, while still ensuring the protection of subjects? He also called for better alignment of regulatory requirements at the EU level and across member states, no rushing through of future legislation, and greater effort in reaching compromises with the EMEA.
Gunnar Danielsson, GCP inspector at the Medical Products Agency in Sweden, conceded that there is a shortage of experienced inspectors. In addition, he pointed out that member states have different priorities, and local regulations, cultures, and traditions vary widely. However, the situation will improve when guidance documents are developed for performing, evaluating, and reporting trials. Key harmonization objectives include standardization of inspectors' qualifications, quality assurance of inspection procedures, joint inspections, shared training programs supported by the EMEA, and a shared database of inspections, he said.
The EC can give guidance and introduce formal procedures, and it engages with member states and stakeholders, but the central role in transposing the directive is played by member states, stressed Erik Helstad, a lawyer in the Pharmaceuticals Unit at the EC's DG ENTR. Infringement procedures may be launched against member states that do not implement or apply the legislation. After assessing a complaint, the EC sends a letter to the member state and asks for clarification. If the member state fails to respond adequately, then a formal letter is sent. Unless the legislation in question is amended, the EC prepares a reasoned opinion, after which the case may be heard by European Court of Justice.
The biotechnology sector is paying particularly close attention to the directive, largely because its future success hinges on the timely registration of new therapies. Industry leaders appreciate the harmonization of administrative aspects, the helpfulness of Competent Authorities, and the pragmatic approach to data requirements for Phase I trials, explained Henk Schuring, director of regulatory affairs for Europe at Genzyme Europe, Naarden, the Netherlands. However, a project team is needed to review the processes, roles, and responsibilities of the main groups. In the post-directive era, the workload of everybody involved in clinical research is increasing, and that is likely to continue for some time, he noted.
Regulators are requesting extensive data, almost similar to what is required for a marketing authorization application, said Schuring. They often demand stability data, validation of analytical methods, certificates of analyses for all batches, and use of ICH quality guidelines out of their scope. A separate viral safety dossier may be necessary, in addition to Investigational Medicinal Product Dossier section 3.2.A.2.
"Authorities, ethics committees, and sponsors are still in transition and in a learning phase. Topics keep coming up as experience is gained for different products, different trials, and different member states," he said. "Industry and regulators need to collaborate closely to maintain and improve the directive and the national legislation, to make it effective and to allow patients speedy access to innovative medicinal products."
Guidance is necessary on the appropriate data requirements for each stage of clinical research, particularly for biologicals and emerging new therapies such as cell and gene therapy, and biotech companies require a full explanation on when a change constitutes "a substantial amendment," Schuring continued. He supports the establishment of a working group to discuss conducting cross-border clinical trials for orphan medicines and developing guidance on trials in small populations.
"The directive has had a profound impact on the clinical trials environment in Europe. Here is an example of one stakeholder, collectively 'the competent authorities,' who took a bold initiative to regulate the practice of clinical research in Europe," summed up Dr. Jean-Pierre Tassignon, EFGCP president and executive vice president of PSI Pharma Support International in Zug, Switzerland. "Don't ask what the directive can do for you, ask yourself what you can do for the directive!"