Pediatric Trials: A New Approach Is Born

The pharma industry won't be the only group rewarded for conducting new pediatric research.

Olli Rehn is not a name well-known across Europe or the rest of the world, but the children of Europe may well have reason to look back with satisfaction when they are adults on the brief encounter this obscure Finn had with European pharmaceutical affairs.

Rehn has recently been projected into prominence as a member of the European Commission, the select group of senior officials who direct European Union business. As of November he will be in charge of enlarging the EU to take on Bulgaria, Romania, Croatia, Turkey, and other countries to the south and east.

At the end of September, however, it was his role as commissioner of industry to announce a new approach to develop medicines for children. After years of reflection, the commission finally came up with its plan for promoting trials in pediatric medicines.

Most of the lengthy preparatory work took place under the aegis of compatriot Erkki Liikanen, the industry commissioner predecessor. But since Liikanen was prematurely called away from Brussels in September to take over as President of the Finnish Central Bank, Rehn was suddenly promoted to step in for him. So Rehn will take the credit-or blame-for how the scheme works.

The proposal aims to address a well-recognized public health problem: more than half the medicines used by children in the EU have not been tested or authorized for their use. As Rehn expressed it, "Our children are denied innovation and they may even be given ineffective or harmful treatment." Market forces are insufficient to supply the medicines children need, he said. So the EU has tried to strike the right balance between meeting public health objectives and strengthening the competitiveness of the pharmaceutical industry.

Since December 2000 the European Commission has been searching for the best solution, including studying U.S. experience and assessing the effectiveness of the European regulation on orphan medicines. It has been juggling how to promote the development and authorization of pediatric medicines without any unnecessary studies in children, and without delaying the authorization of medicines for adults.

For a medicine still under patent, a new requirement will be to present results of studies in children conducted according to an agreed plan, at the time of application for marketing authorization. This requirement will also apply when companies apply to extend the use of the product, for example by using it at a different strength. However, this will be waived for medicines developed for adults that are not useful for children. In addition, it may be safer to study some medicines in children only after studies have been conducted in adults. In this situation, there will be a deferral starting or finishing studies in children.

The Commission believes the pharmaceutical industry be rewarded for conducting the additional studies, so a six-month extension of the supplementary protection certificate will be granted-in effect an EU-wide patent extension.

For orphan medicines, the situation is different. Not all orphan medicines are patented, and they already get 10 years of market exclusivity. So orphans will receive an additional two years of market exclusivity in addition to the 10 they already have.

The situation is admittedly more difficult to fix for off-patent medicines, because such products have often been on the market for many years via multiple license-holders, including generic companies. They have no intellectual property rights, and yet they may be of great therapeutic value to children. So the proposed solution is that new off-patent medicines specifically developed for children should be granted a new type of marketing authorization-the Pediatric Use Marketing Authorisation, or PUMA. Newly developed but off-patent products can be granted 10 years of data protection on any newly conducted studies. In addition, the PUMA allows the use of the existing brand name, which is of obvious commercial interest to the industry.

In terms of data requirements, the PUMA will, for the first time, allow a generic-type application to be combined with the new studies in children. This should make it easier for industry to develop these medicines.

Pediatric committee planned
There will also be measures applying to all medicines, on- or off-patent. One will be the establishment at the European Medicines Agency of a new expert pediatric committee to scrutinize companies plans for testing medicines in children. This will be designed to ensure research is of high quality and only conducted when it will benefit children. In addition, a European network of investigators and trial centers with expertise in children's medicines will be set up to help the conduct of studies in children. The European Medicines Agency will also provide-free of charge-scientific advice on how to conduct studies in children.

To ensure high-quality information about the safe and effective use of medicines, an inventory will be established of the therapeutic needs of the children of Europe to help identify where products are needed. New product labelling requirements will ensure children, parents, and doctors can make informed decisions about treatment. And a database of studies in children will be set up to ensure studies are not duplicated, and so the results of studies are put to best use. Industry will be required to submit to the authorities study reports they already hold on use of their medicines in children, to maximize the utility of existing data and knowledge.

Strengthened safety measures
There will also be enhanced safety monitoring for marketed products, to ensure that the newly developed products are closely followed once they are on the market.Part of the proposal also foresees a separate initiative to create an EU pediatric study program called Medicines Investigation for the Children of Europe (MICE), to fund research leading to the development and authorization of off-patent medicine for children.

The proposal immediately won support from European drug industry organizations. The European Federation of Pharmaceutical Industries and Associations welcomed it as an important step. "Overall, we must work towards an ethical, effective, and favorable environment in Europe for pediatric research and development of specific medicines to treat diseases in children. The adoption of a EU legislative framework is an opportunity to improve public health and strengthen Europe's science base," said Brian Ager, director general of EFPIA. "Industry, regulators, patient groups, doctors, pediatric societies and EU researchers all have a role to play. The goal is to foster pediatric research in Europe for medicines adapted to the needs of Europe's children." EFPIA said it would continue to work for appropriate regulatory and incentive measures to be put in place to stimulate pediatric research and development in Europe and fast access to innovative medicines for patients of all ages.

The Association of the European Self-medication Industry, representing manufacturers of nonprescription medicines in Europe, welcomed the proposal. "The Commission has chosen a reasonable approach in the area of non-prescription medicines, encouraging relevant research without forcing unnecessary studies," declared AESGP's Director, Dr. Hubertus Cranz. "Although some details may need clarification, the proposal is going in the right direction."

The proposal will now start its progress through the EU's legislative machinery, with examinations by the European Parliament and national ministers in the EU Council. The earliest that the proposal is likely to become law is late 2006. Olli Rehn will by then be enmeshed in the intricacies of EU accession negotiations with Turkey and the countries of the western Balkans. But children being born today may stand to benefit throughout their lives-for themselves and for their own children's children.

Sidebar: The Reasoning Behind the Rewards
The European Commission has been hard-headed in its assessment of what will be needed to make a new system work. It has set out the arguments explicitly in documents accompanying the proposal. In summary, its reasoning for providing rewards is as follows:

"Intervention is necessary as the forces of the free market have failed to deliver medicines for children. However, for new medicines and patent-protected, authorised medicines, a requirement without rewards would place the entire burden of this public health issue on industry and could reduce or hamper innovation for adults. A system of reimbursement to industry for the costs of developing, authorising and marketing medicines for children is theoretically possible. However, such a system would be near impossible to administer. Such a system would require, in particular, the costs of research and development of medicines to be known in advance. It would also require a precise knowledge of the market before the product is launched. Furthermore, the largest sales of medicines are usually up to 10 years after first marketing, as a product nears patent expiry. When, therefore, would reimbursement be calculated and how could the sales for children be accurately divided from the sales for adult use? On this basis the Commission has opted for a far simpler system based on an existing EU-wide instrument: extension of the supplementary protection certificate (SPC). Extension of the SPC will provide for a mixed reward and incentive. By extending the patent life of the active moiety, generic competition will be delayed for the entire product range based on that active moiety and this will occur at the end of the patent life when sales are generally at their greatest. For successful products, whether sales success is in child or adult markets, the SPC extension will result in increased sales for the innovator company that may significantly outweigh the costs incurred as a result of the requirements in the draft pediatric regulation. However, for other, less successful products, the SPC extension may not fully compensate the costs incurred as a result of the requirements. Overall it is likely that for most products, industry will be more than compensated for their costs. In this way, the SPC extension can be viewed as a mixed reward and incentive."