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In many parts of the globe, intended and actual effects of GCP legislation often differ.
In many parts of the globe, intended and actual effects of GCP legislation often differ.
Its a truly global village now for clinical trials, as Tom Gallacher of GlaxoSmithKline remarked to this columnist during a European Forum for Good Clinical Practice (EFGCP) conference in Brussels at the end of March. So even if the EFGCP has an understandably European focus, its latest conference demonstrated how wide the European vision must be in these international times to ensure its focus is accurate.
Alongside the familiar European faces on the platform sat such figures as Delon Human of the World Medical Association, Vladimir Lophakin of the World Health Organization, Pierre Effa of the Pan-African Bio-ethics Initiative, Melody Lin of the U.S. Office for Human Research Protections, and Vichai Chokevivat of the Thai Ministry of Health.
The meeting aimed to locate GCP inspections in Europe in an international context, by looking at how research participants in clinical trials are protected elsewhere in the world.Jean Saint-Pierre of the Canadian health inspectorate pointed out how Canada adopted a new clinical trials framework in 2001 that included formal integration of GCP and the gradual implementation of an inspection program. Results from the initial voluntary phase showed deficiencies mainly in terms of incomplete records, insufficient systems and procedures, and failings in informed consent.
Patricia Saidon of the Argentinian medicines control agency, a key figure in the pan-American moves towards drug regulatory harmonization, recounted how patient enrollment in international multi-center trials was rising rapidly in the region, with a concomitant rise in the number of investigational sites, investigators, committees, and research-related staff. Divergences in implementation of GCP have been identified, covering protocols, informed consent, and ethics committees composition, responsibilities, and functions.
A Latin American working group on GCP is aiming to promote greater harmonization of clinical trials legislation across the region, which is not covered by the EUUSJapanese International Conference on Harmonization. It is also trying to set up training, evolve a database of clinical trial authorization requests (and decisions), and assess how inspections are carried out.
It was refreshing to hear Benjamin Kuo of the main Taiwanese institutional review board frankly admit that one of the key incentives for raising standards of ethics review was, alongside enhancing the protection of human subjects, to increase Taiwans competitiveness in attracting multicenter trials. The board of which he is a member is independent and offers an efficient and high-quality review service, he claimed. Its approvals have been accepted by more than 40 local ethics committees in hospitals in Taiwan, and demand for its services is growingmostly in Phase III trials.
Olga Kubar from the Pasteur Institute in St. Petersburg recounted how the Confederation of Independent States (CIS, most of the former Soviet republics on the fringes of Europe, but also stretching way beyond it) has created a regional forum for ethics committees, which in turn has developed a model law on protection of human rights and dignity in biomedical research. This is built in part on the GCP rules that many of the former Soviet states have taken on board, she said. They were themselves inspired by the study of European, United States, and international models, and discussions with representatives of EFGCP, the European Union, and WHO. Armenia, Belarus, Georgia, Moldova, and Russia have signed the Council of Europe Convention on Human Rights and Biomedicine, and Georgia has already ratified it.
Human rights in practice
But at the same time, she acknowledged, there is a lively debate going on across the CIS on the implementation of this human rights-oriented legislation. In respect of clinical trials, it provides for protection of human dignity, rights, and safety, as well as of research. In practical terms, it is intended to ensure credibility and reliability of research results. But it regards ethical and scientific review of biomedical research to be the basic measure for protection of individuals and communities taking part in research. It places high priority on informed consent and safety information, and makes special provision for research conducted in emergency situations, epidemiological and social clinical research.
The timetable Kubar presented suggests that between now and September the legislative project will be under review in the parliaments of the CIS, leading up to a meeting in October of clinical trial experts from across the region and from Europe and WHO. In principle, this should lead to approval in the CIS ministerial council in December, and to adoption and implementation in the national legislation of each of the CIS through 2005.Again, as was explicit in Taiwan and implicit in many other parts of the world, where the prospect of attracting international clinical trials is an incentive to upgrading legislation, the purpose of the new law is to express agreement on a high level of moral standards and aspirations, to promote confidence in international cooperation in clinical research both inside the CIS and beyond, and to bring national legislation in the CIS into compliance with international standards, according to Kubar.
Gaps at home too
Meanwhile, theres still plenty of divergence back home in Europe, even though the new EU clinical trials rules were to come into effect at national level on 1 May. Professor Tamas Paal, Director General of Hungarys National Institute of Pharmacy, is apprehensive about the enlargement of the European Unionwhich also was to happen on 1 Mayand which brings 10 new member states into the EU: Poland, the Czech Republic, Hungary, Slovakia, Estonia, Latvia, Lithuania, Slovenia, Cyprus, and Malta.
It is not, he told ACT, that all the new member states are at a lower level in clinical trial legislation than the 15 current member states they will join. Some of the new members are well up to standardand even better than some existing members, he claimed. The Czech Republic, Slovakia, and Hungary have a good level of implementation of clinical trial rules, and a long tradition of ethics committees with a high scientific level, which have grown out of the traditional drug committees of communist times. It is also possible for these countries to adapt easily to the new EU system of a central ethics committee, he said.
By contrast, Paal sees Poland as less well organized, with many different ethics committees, but little systemization among them. What concerns him is the prospect of even greater unevenness across the enlarged 25-member EU than there is at present. Diplomatic delicacy inhibited him from naming the current EU member states who contribute to the unevenness he perceives, but he did spell out what he saw as an inescapable obligation: Even if you dont like the new EU clinical trial rulesand they are certainly not sponsor-oriented or investigator-orientedyou have to obey them, he insisted.
One of the areas where further evidence of unresolved European divergences also emerged during the EFGCP meeting was in the approaches to who does what in terms of ethical and scientific review. It is no caricature to depict this as a clear split across the member states: even Europes top regulatory officials accept that the differences are significant. For instance, Italy and the Netherlands tend to give their ethics committees serious scientific responsibilities too, while in the United Kingdom or Germany the authorities focus on the scientific review and the ethics committees confine themselves to ethics.
One of the conference speakers, Helena van den Dungen of the Dutch Healthcare Inspectorate, said that ethics committees in her country conduct both scientific and ethics review. The committees have official status as part of the government apparatus, she pointed out. The authorities do only a marginal check on GCP, she said. Even the investigational medicinal product dossier goes to ethics committees.
A similar scenario applies in Italy, said Umberto Filibeck of the Italian Ministry of Health. Ethics committees have official status as local government public bodies, and they assess the scientific as well as the ethical justification for trials in most cases, except for products in areas such as gene therapy.
Gerd Werner, head of the inspection service at the Paul Ehrlich Institute in Germany, staunchly defends the merits of separating scientific from ethical review. The medical aspects of a trial should be subject to scientific assessment from a medical standpoint, he told ACT. The role of the ethics review is different: to check on the adequacy of the objective and the mechanics of the trial itself. Even after implementation of the new EU clinical trial rules, Germany will maintain a clear distinction between scientific and ethical review. We will keep them separate, said Werner. Inspections should be done by the health ministry officials, not by ethics committees.
Bridges still to be crossed
Even the most energetic advocates of harmonized European clinical trial regulation are obliged to admit that some 15 years after the process started, it is still far from complete. EFGCPs description of its own conference program remarked that while the European development of systematic Good Clinical Practice oversights through inspections and ethical review is taking on an increasingly important role in research participants protections, within Europe and internationally, Europe has responded to this increased responsibility of regulatory authorities by actively developing national systems of GCP inspections and ethical review. Politely, EFGCP also concedes that these national systems have a strong European and international dimension, but they remain, nonetheless, national systems.
The new EU rules, with their increased emphasis on ethics, government oversight, and quality assurance, have produced a heightened awareness of the importance of regulatory oversight of clinical research and of patient protection processes. But each component of the clinical trial community, including public and private funders of research, investigators, ethics committees, and patient organizations, looks at things from a different perspective. The question remains open as to how far the development of European GCP oversights is contributing to real protection of research participants, and meeting the expectations of sponsors, investigators, and patients within and without EU borders.
One Olympian observer of this long European GCP gestation looked back with philosophical resignation at the realities that have led to the continuing divergences. The European Commission realized years ago it would be impossible to impose harmonized clinical trial rules directly on the EU member states, he reminisced to ACT. Instead, he suggested, the Commission opted to use a more indirect approach: winning political approval for a less challenging framework which would need filling in with subsequent technical guidelines. The Commission, according to this plan, would then be able to impose its view through the guidelines, smuggled in via the Trojan horse of a framework directive.
The plan has backfired, said this seasoned observer. The political agreement was obtained for the framework directive, but when it came to filling in the gaps with the detailed guidelines, the Commission found it was still powerless to effect any real approximation. For a start, there was no consensus on which GCP model was to form the basis for the harmonized approachfrom the growing range of earlier EU rules and subsequent exercises in the International Conference on Harmonization, the World Health Organization, and elsewhere.
Partly because of this lack of consensus on a model, and partly because of deep-rooted traditions in the member states, the Commission got bogged down when it consulted (as it was required to do) with the member states on the guidelines.
Instead of finding a soft legislative underbelly, the Commission found itself confronted by the fangs of member state intransigence. In consequence, the guidelines that emerged from the consultation process were an accumulation of existing practice rather than the slimmed-down one-size-fits-all approach that the Commission had been hoping to slip into place. As a result, according to this expert, the member states emerged with even more autonomy than they had before.
A sobering conclusion indeed as the new EU clinical trials rules come into effect!