Another Step Toward EU Pediatric Trials

European Union ministers gave their broad backing to the proposed rules on pediatric medicines at their Social Affairs Council in March. As regular readers of this column will know, the two years of intense discussion so far on this proposal have been geared largely toward stimulating clinical research on products for children and ensuring that medicines used to treat children are appropriately authorized for use in pediatric populations.

Peter O'Donnell

The council agreed with the proposal's objectives and with many of the views expressed by the European Parliament, which gave a first reading to the proposed rules last September. But it has added some changes, notably about improving research into pediatric use of off-patent medicines, keeping pediatric products on the market, and availability of information.

"Provision should be made for research into the pediatric use of medicinal products which are not protected by a patent or supplementary protection certification," says the council—and it adds that this should be financed under EU research programs. The funding would be delivered through the EU's framework programs for research "or any other [EU] initiatives for the funding of research."

The council has decided to insert a new article to ensure that products stay on the market if they have a pediatric indication that has benefited from the rewards in the regulation. This is in line with similar calls from the European Parliament, but goes further, notably in systemizing the possibility for interested third parties to continue marketing the product, and in imposing a deadline for informing the agency of the intention to discontinue placing a product on the market. When periods of protection have expired on a pediatric product and the marketing authorization holder intends to discontinue it, he "shall transfer the marketing authorization or allow a third party, which has declared its intention to continue to place the medicinal product in question on the market, to use the pharmaceutical, preclinical, and clinical documentation contained in the product file." To facilitate transfer, the marketing authorization holder will have to inform the agency of its intention to discontinue placing the product on the market at least six months before the discontinuation.

Transparency

The beloved EU concept of "transparency"—or what normal people call information—gets a boost from the council too. It supports the introduction of transparency into the European pediatric clinical trials register foreseen by the regulation. In order to increase the availability of information on the use of medicinal products in the pediatric population, and to avoid unnecessary repetition of studies in the pediatric population that do not add to the collective knowledge, says the council, the European database provided should include a European register of clinical trials of medicinal products for pediatric use, comprising all ongoing, prematurely terminated, and completed pediatric studies conducted both in the EU and in other countries.

Database details

The council, however, says that clarification is needed about what is to be included and how the details would be entered. The database shall include, says the council, clinical trials carried out in non-EU countries that are contained in an agreed pediatric investigation plan, in addition to European clinical trials. For trials carried out in non-EU countries, the full details are to be entered into the database by whoever has submitted a pediatric investigation plan.

What the Pediatric Regulation Will Do

The agency is to make public part of the information on pediatric clinical trials entered in the European database. This will include details of the results of all pediatric clinical trials submitted to the competent authorities, even when terminated prematurely. These results have to be submitted without delay to the agency by the clinical trial sponsor, the marketing authorization holder, or the recipient of the agency review of the pediatric investigation plan.

But the council diverges from the European Parliament on how to treat ongoing trials. The parliament wants to open the possibility to provide information on pediatric studies still underway. The council says this is not necessary, and points out that the proposal does not require the completion of all pediatric studies at the time of application for marketing authorization: There is a "deferral" provision that allows for delay in the initiation of pediatric clinical studies so as to ensure that the studies are only done when it is safe and ethical to do so.

A deadline should be set for the submission of a pediatric investigation plan, believes the council, in order to ensure early dialogue between the sponsor and the pediatric committee on whether studies are required and, if so, the type of studies and their timing compared to studies in adults. It is, however, a deadline only to submit a draft plan—not a deadline for the initiation of studies. In addition, the plan may contain a request for a deferral of the initiation or completion of studies.

The pediatric investigation plan may subsequently be monitored, and the council considers this valuable as a mechanism for ensuring continuing dialogue between the applicant and the pediatric committee during product development. Trying to force early pediatric studies of a product—as the parliament is suggesting—could backfire and impede innovation in pediatric therapeutics, with negative consequences for public health, the council believes.

Grandfathering pediatric plans

Legally speaking, it is impossible for pediatric studies completed prior to the entry into force of the new rules to be included in the pediatric investigation plan. But so as not to discourage current research, existing and ongoing studies at the time of its entry into force will be eligible for inclusion once the regulation is adopted.

Members of the pediatric committee do not need to have international-level experience and knowledge of the pharmaceutical industry, says the council, but—unlike the European Parliament—it does not consider the committee to be primarily responsible for the ethical assessment of the pediatric investigation plan.

The European Commission, which proposed the new rules in 2004, is happy with the council's position, and to finalize the process, the European Parliament now has to give the draft a second reading—probably this summer.

Council reservations

But it has not all been plain sailing—and choppy water may still lie ahead. At the March council meeting, Poland voted against the position that the other 24 member states shared. It said that like its council colleagues, it was in favor of measures to promote the development of research into medicines for children, and to provide the pediatric population with medicinal products that are safe and effective. But it felt the incentives offered were too generous, and the opportunities for generic copies were too restricted. Thus, it rejected the proposed extension of protection periods for original products, "since it delays the marketing of cheaper generic products, thereby restricting patients' access to pharmacotherapy and increasing expenditure in national health care budgets. Poland considers that this conflicts with the overriding aim of this regulation."

And an improbable pairing of Latvia and Belgium expressed similar reservations, without actually voting against the proposal. A system of rewards and incentives is necessary to achieve the objective, but these "should be commensurable with the costs incurred by manufacturers and result in the lowest possible impact on the state budget and patients."

While the pediatric rules are still making their way through the EU legislative pipeline, the final version of the new rules on conditional marketing authorizations for medicines appeared in March. These formalize arrangements for bypassing the normal preauthorization procedures. "To meet unmet medical needs of patients and in the interests of public health, it may be necessary to grant marketing authorizations on the basis of less complete data than is normally the case and subject to specific obligations," says the new rule.

These conditional marketing authorizations will be granted only where the clinical part of the application dossier is less complete than normal. But clinical trial staff need not fear that they are to be rendered redundant by conditional marketing authorizations. The new rules make clear that although the data upon which an opinion on a conditional marketing authorization is based may be less complete, the risk–benefit balance should be positive, and the benefits of making the product immediately available should outweigh the risk inherent in the fact that additional data are still required.

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