Pediatrics and Ethics Predominating in 2005


Applied Clinical Trials

Applied Clinical TrialsApplied Clinical Trials-03-01-2005

Will the new pediatric and ethics initiatives receive enough funding to make them truly work?

Will the new pediatric and ethics initiatives receive enough funding to make them truly work?

The new year is already proving to be action-packed in Europe as far as discussions about clinical trials are concerned. In the space of four days at the end of January, Brussels hosted two big conferences on major areas of development for clinical trials: the European Union proposal for new rules to encourage clinical trials in pediatric medicines, and the challenges that research ethics committees have to face as their responsibilities increase.

The pediatric medicines meeting, organized by the European Forum for Good Clinical Practice, examined how the September 2004 legislative proposal1 is likely to impact pediatricians, clinical researchers, national health care systems--and of course children.

The proposal is still under discussion within the European Parliament and the EU Council of Ministers, and much of the debate is focused on how to balance the need for appropriately tested medicines for children with the many ethical and practical constraints that conducting trials on children involves. But there is another important strand, too: how to provide incentives for sponsors to conduct expensive and complex trials that market forces alone are not sufficient to generate.

The official view
For Peter Arlett of the European Commission, the key consideration in reconciling these tensions has at all times been the health of children. He stressed the need for input from ethicists and patient representatives in all discussions of testing plans, and for plans to be approved only if they are in the child's best interest. To assist in this process, new EU guidelines on ethics in pediatric trials are needed, he insisted, indicating that work would start on them early in 2005 in the advisory committee already created within the broad framework of the existing EU clinical trials rules.

Nathalie Seigneuret of the European Medicines Agency in London justified the need for legislation partly on the grounds that industry is just not interested in the pediatric market, and partly because at present information is lacking and medicines are being prescribed to children without proper information or formulations. A new legal framework would offer better protection to children, avoid replication of unnecessary trials, and result in more informed decisions on how and when to perform trials on pediatric medicines.

The academic view
The academic community sees both good and bad in the proposal. Gerard Pons of Rene Descartes University in Paris welcomed the prospect of a more rational approach to evaluating pediatric medicines. But he expressed alarm at what he saw as major deficiencies: there will be no obligation on companies to conduct pediatric investigation of new medicines; there will be inadequate incentives to study medicines that no longer have any intellectual property protection, and there will be insufficient transparency over the results of pediatric trials. He summarized his key requirements as "more money for old drugs," and "more research."

Fred Zepp of the Johannes-Gutenberg-University in Germany suggested that innovative academic research can provide helpful noninvasive technologies that can overcome some of the current hurdles in pediatric trials. But above all he urged the creation of a European network for drug investigation in the pediatric population--modeled on, or at any rate partnered by, the PAED-Net network already established among university researchers in Germany.

The patients' view
The expectations of children and their families were developed by Yves le Cam of Eurordis--the European Organisation for Rare Diseases. The EU proposal is valuable, he said, but needs improvement. He warned against creating an excessively complex bureaucratic structure for assessing sponsors' pediatric investigation plans: "Heavy procedures would be discouraging, particularly for smaller firms," he said. Instead, the EU authorities should devote more resources to identifying unmet pediatric needs and actively inviting investigation plans that could meet them--as well as providing appropriate financial backing: at present, "The absence of adequate financial support in the Regulation seriously undermines the scope," he said. And the rules should provide for wider availability of data from right around the world, with commercial confidentiality taking second place to the need to avoid duplication of trials.

The industry view
Industry's view inevitably focused principally on the need for an efficient system of incentives. As Brian Ager of the European Federation of Pharmaceutical Industries and Associations put it, the objective must be "an ethical, effective and favorable environment in Europe for pediatric research and development of specific medicines to treat diseases in children."

Klaus Rose of Novartis listed the complexities of the challenge of integrating pediatric aspects into the general drug development process. Legislation--impending in Europe and already in force in the United States--does not fundamentally change the research aims of pharmaceutical companies, he observed. Essentially, legislation will lead only to additional inclusion of children into the development of medicines that are primarily targeted at adults. He warned against the risk of merely expanding bureaucratic intervention. And he called for compatibility in the pediatric requirements of U.S. and EU authorities: "Global companies' teams want to be prepared for the upcoming EU legislation," he said. But at present there is nobody in the EU who can provide clear answers. At the very least, a transitional solution should be envisaged, he urged.

Some industry participants, however, had a different angle of the priorities. Greg Perry of the European Generic Medicines Association called for greater emphasis on the development of off-patent products for small populations, and a strictly proportional reward system for in-patent products so as to maximize resources available for all pediatric development. Otherwise, he warned, there is "a danger of member states paying disproportionate prices" for trials of patent-protected products, and neglecting development of off-patent products.

The international dimension was also prominent in the discussions at the EFGCP meeting. The list of speakers ranged across the United States, Japan, Africa, the World Health Organization, and the World Alliance of Patient Organizations. As Francis Crawley of EFGCP told ACT, the view has to be global, because "Kids are everywhere."

Ethics and pediatrics
What Crawley is also concerned about, however, is that a regulatory framework will be created faster than the ethics framework that should accompany it. And, as everyone who has followed the genesis of the EU's clinical trials rules knows, the concerns over ethics are widely shared by the European Parliament, too. Already the Parliament has called for particular attention to the ethical aspects of pediatric medicine development: when they start their in-depth assessment of this new proposal, they are likely to be insistent on eliminating any risk of exploitation of children, and to want some cast-iron assurances over high levels of protection of the patient.

Ethics at local level
Ethics was at the heart of the other major clinical trials event in Brussels in January--the challenges that research ethics committees (ECs) have to face as their responsibilities increase. Under the title of "Research Ethics Committees in Europe: Facing the Future Together," the European Commission hosted some 350 representatives of local and regional ECs from right across Europe. The discussions focused on how to promote pan-European dialogue, awareness-raising, networking, and understanding between researchers, regulators, and ethicists. The aim was to encourage effective and more consistent ethical evaluation of research at local, national, European, and international levels, while also taking account of cultural differences.

The meeting was timely, because the responsibilities of ECs are evolving--particularly under the impact of the EU's clinical trials rules, and its requirements for a higher degree of cooperation on multicenter trials. And it was, in its way, the first of its kind. The complexities of ethical review have been frequently discussed at European level, but this has invariably taken place so far among regulators, researchers or sponsors. EU funding of this conference made it possible to bring members of ethics committees themselves into the picture, by flying them in and putting them up for two or three nights in Brussels.

Most of these committees are working independently. So although the national and European regulatory framework requires that research activities should not contravene fundamental ethical principles, the EC methods of operation vary widely within each country and from country to country.

The debates over two days examined the state of the art, and the different practices, obstacles, and pitfalls. Many more questions than answers were revealed by the discussions, making it clear that there is still a major task to be undertaken to provide clearer information to ethics committee members, and to align practices more closely.

The commission spoke boldly at the outset of the meeting of its aim of identifying future initiatives, actions, and activities in this direction. As Janez Potocnik, Commissioner for Science and Research, said in his introduction, "We are well aware that the work of these committees, your work, is essential to the integration of ethics into research practices. But we also know that, in several member states, there are issues that need to be addressed, such as the lack of financial resources, training needs, sharing of best practices and lack of appropriate national or supra-national legislation."

There is much to reflect on from this meeting--and this column will doubtless return to some of the key issues that emerged. But there was one refrain that was heard more often than any other: the lack of on-the-ground resources for committees. The coming months will reveal whether the participants at the meeting are able to organize themselves in such a way that more funding is made available, either at European or national level, to allow the committees to develop as they need to. Without that, the discussions may remain just discussions.

1. Proposal for a Regulation of the European Parliament and of the Council on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/83/EC and Regulation (EC) No 726/2004; European Commission COM(2004) 599 final, 29.9.2004 (for full text, see

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