Agreeing on Pediatric Trials Is No Child's Play

Debate in the European Union is reaching a critical phase on the 2004 proposal from the European Commission for boosting the development of pediatric medicines.¹

Peter O'Donnell

The European Parliament's committee responsible for health is developing its position on the proposals. The latest draft of its thinking contains numerous calls for change, many with a pragmatic pro-research flavor.

For instance, the purpose of the new regulation should be widened, it says, not just to increase the development of medicines for use in children, and to ensure the quality of their research and information, but also to improve access to them—which in effect means reducing the national obstacles to new product launch. "New medicinal products for paediatric use should be made available with the least possible delay in all member states," according to the Parliament's Françoise Grossetête.

The new legislation's wording should also be improved to avoid the risk of new requirements for children's medicines unnecessarily delaying the introduction of medicines for adults. "Paediatric investigation plans should be submitted early during product development, in time for studies to be conducted in children," and before marketing authorization applications are submitted—but only "wherever possible."

The requirements for early launch of pediatric products should be slightly eased—to allow three years after grant of a pediatric indication, rather than the two years the commission proposes, and to allow exemptions where health grounds merit it. "Allowance should be made for exceptional circumstances warranting a deferral," says Grossetête.

The Pediatric Proposals

The promised incentive of a six-month extension of patent coverage for developing pediatric indications for existing products should be available not only for authorized products, but also for products that have been submitted for marketing authorization.

The requirements on labeling should be more flexible, says Grossetête. Where authorization is granted for a pediatric indication of a product on the basis of new trials, the results of those studies shall be included as the commission proposes, in the summary of product characteristics and, if appropriate, in the package leaflet of the medicinal product. But only "provided that the competent authority deems the information to be of use to patients," she adds. Her reasoning is that some of the information in the summary of product characteristics needs to be made clearer, "and the package leaflet must not be cluttered up with irrelevant information which would make it more difficult to understand."

The special marking to be created for pediatric versions of an existing product should be used retroactively, so that it applies to medicines authorized prior to the regulation, and only covers pediatric indications. Restricting the marking system to new products "could serve to discriminate against paediatric forms placed on the market prior to the adoption of the regulation. Furthermore, patients might find the marking system difficult to understand if it was not used in all paediatric medicinal products placed on the market," she says.

Some of the Grossetête amendments focus on regulatory authorities more than researchers. For instance, she urges that public funding should be made available for pharmacovigilance, "with a view to ensuring total independence." The funding should be "commensurate with the tasks assigned to competent authorities." As she observes, the supervisory activities of competent authorities will be stepped up as a result of the new tasks assigned to them. Provision needs to be made immediately for the funding that will be required for the system to work properly.

Grossetête is also responsive to widespread calls from the research community and patient associations for further action. She is calling for a binding EU commitment to early creation of a specific European program for research into medicines for children, to provide support for studies on existing products or active substances that are no longer patented. The program would be run by the European Medicines Agency in London, via calls for proposals. It should, she insists, provide "a level of funding that will cover all, or at least a very large part, of the costs generated by the studies requested."

"Before any studies are embarked upon, we need to know whether there is a need for them and whether the prospective medicinal product will be of benefit to children or not," Grossetête stresses. She accepts entirely the view that only clinical trials that are absolutely necessary should be carried out, and trials that have already produced results should not be repeated.

And she sees the pediatric committee proposed by the commission as "the cornerstone of the system." This committee will give its views on every pediatric dossier, and be involved in investigation plans in partnership with applicants. So part of her objective is to establish the committee's tasks clearly, including proper monitoring of pediatric investigation plans, and identifying specific needs in the pediatric sector.

The health committee should reach agreement by midsummer on its position on the proposal, so that the parliament can give its formal view later in the year.

Discussions among governments

Meanwhile, the other half of the EU legislative machinery, the Council of Ministers, is also examining the proposal. The health ministers of the 25 member states held a broad discussion on the draft regulation when it met in Luxembourg on June 3. The council is focusing on two aspects: whether the planned extension of patent terms provides the right incentive for the drug industry to invest in pediatric research, and what degree of access should be given to information on pediatric trials.

There is an emerging consensus that improved patent rights offer a useful incentive. But there are differences among member states on the length of the extension (some feel that six months is too long), and what conditions should be attached to it (some urge a review of the system after 10 years, others want more frequent reviews). The European generic industry has been lobbying strenuously—and, in some countries, successfully—against introducing further measures that could unnecessarily delay the introduction of copy products.

There is also broad agreement on the need for wider access to clinical trial results, so as to avoid unnecessary studies being conducted. But there is less agreement on just how wide the access should be, and to what sort of results.

Industry views

The European Federation of Pharmaceutical Industries and Associations (EFPIA) supports the idea of "proper economic incentives," and of a pediatric R&D infrastructure in Europe. But it has warned against measures that could result in "premature or unwarranted testing in children," or delay the availability of medicines for other populations. It is also conscious of the disincentive risk of conducting clinical studies on new medicines for children in Europe now. Since the new measure will not come into effect before the end of 2006 at the earliest, it should be made clear that pediatric investigations initiated prior to that should also be considered as part of an agreed pediatric investigation plan.

EFPIA says the principle of linking the submission of pediatric and adult results is contrary to scientific and ethical standards. The applicant should instead be required to comply with a timing agreed, on a product-by-product basis, by the proposed Pediatric Committee. It says that the requirement to submit a pediatric investigation plan no later than upon completion of human pharmaco-kinetic studies in adults is irrational. At that early stage only a vague outline of a pediatric plan is possible, which will later require substantial modifications—and in any case pharmacokinetic studies may be conducted throughout development.

EFPIA fears the current formulation of the incentive is too limited, and that an extension of exclusivity should relate not just to the Supplementary Protection Certificate, but patents or regulatory data protection too. "A six-month fixed-term incentive is an absolute minimum," it says.

Patient association concerns

The proposal has been welcomed in principle by many European patient associations too. But there are some serious concerns over what is seen as an excessive focus on industry-based re-search, leaving academic and small-scale research virtually unprovided for, as well as inadequate urgency in the response to the needs of many sick children.

"The proposal has not been set in the wider debate of what children need," according to Hildrun Sundseth, a lobbyist well-respected in the EU for her 20 years work for MSD, and who has recently become head of policy for the European Cancer Patient Coalition. "It's been conceived in the framework of medicines for adults, and that's the wrong approach. There are many pressing needs for medicines specifically for children, in cancer, rare diseases and hereditary diseases, and this regulation largely ignores them."

In particular, she wants a stronger link made to the EU's scientific research programs (a new one for the period 2007–2013 is currently in preparation), and more coordination within the European Commission and its separate departments for policy on health, research, and industry.

She also wants much wider access to clinical trial information than is currently envisaged. "It should be on a single database that is publicly accessible, and should cover all trials, even in Phase I," she says.

And she wants faster action: there is no need to wait three years—as the current text proposes—for the pediatric committee to draw up a list of therapeutic needs for children. That should be done immediately, by the commission, and by experts already sitting in the pediatric working group of the European Medicines Agency, she urges. That way, the pediatric committee could use its resources to identify research priorities from that list as soon as it comes into being.

The next stage

Once the European Parliament has given its first formal view on the proposals—perhaps as early as this July—the Council of Ministers will reach a definite position, too. If there are not too many divergences, a second reading could be completed in late 2005 or early 2006, with the new regulation coming into force in late 2006 or early 2007. But if Parliament and Council disagree, or if the commission decides to adapt its proposal significantly in the light of the conclusions of the current debates, that timetable may be stretched out by at least another six months. As this column has remarked before, it is slow progress for a concept that has been around for five years now.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.

References

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; http://

dg3.e.udra.org/F2/Paediatrics/index.htm

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