EU Pediatric Rules ?Creeping Like Snail?

Among the many current regulatory projects in Europe on medicines development, one that has lain fallow for a year or so is now emerging again into the limelightthe promotion of clinical trials on pediatric medicines. But progress is slow enough to bring to mind the child who the melancholy Jacques describes with satchel and shining morning face, creeping like snail unwillingly to school.¹ There has still been no full discussion in the European Union about how to turn the idea into a reality. Instead, the latest move is that the EU has announced plans to carry out an extended impact assessment of a draft European Commission proposal on medicinal products for pediatric use.

Extended impact assessments are all the rage in Brussels nowadays. The idea is to check out in advance whether proposals are sound, rather than wait until the law is on the statute book and then find out it doesnt work as intended. The aim of this one is to evaluate the economic, social and environmental impact of the different elements of the Commission proposal as well as the impact on sustainable development.

No mean feat. And because the Commission doesnt feel up to the task itself, it is farming the work out. It has just published a call for tenders to do the job.

The Commissions draft proposal for medicines for pediatric use still has no legal status, as it remains an internal consultative document. It sets out a system aimed at stimulating development of products adapted to the needs of the pediatric population through a mixture of requirements and incentivesand the EU underlines the importance of striking the right balance between the two.

Now the EU wants to analyze how effectively that system might work. So it wants someone to study key elements of its outline proposal. Under particular scrutiny will be:

• the requirement to include the results of an agreed pediatric evaluation plan as part of an application for a marketing authorization.
• the incentive of an extension by six months of the duration of the period of supplementary patent protection (by comparison with the alternative of an extension by six months of the period of data protection).
• the creation of a priority list of products for which there is a need for adaptation for pediatric use.
• the creation of a European network with specific expertise in the performance of trials on pediatric populations.
• the requirement to collect long-term safety information in the pediatric population.
• the publication of information on trials conducted in the pediatric population.
• the establishment of a pediatric study fund and alternative means of financing the fund.
• the establishment of a new category of marketing authorizationthe pediatric marketing authorizationassociated with a five-year period of data protection.
  In addition, the EU wants a comparison with what would happen in a no policy change scenario.

The contract is due to be signed in September this year, and to run for six months.The EU knows why it wants to move ahead. It has already recognizedas have some individual countries, and notably the United Statesthat the absence of pediatric information in marketing authorizations poses risks for children:

• Inadequate dosing information can create adverse reactions that could be avoided.
• The lack of pediatric safety information risks age-specific adverse reactions.
• The absence of pediatric testing can lead to ineffective treatment through underdosing, or prevent access to therapeutic advances, because physicians choose to prescribe existing, less effective medications in the face of insufficient pediatric information about a new medicine.

If pediatric formulations are not developed, younger patients that cannot take the adult formulation may be denied important new therapies, or they may have to take extemporaneous formulations that may be poorly or inconsistently bioavailable.

Says the EU
The problem persists because the ethical obligation to ensure that the paediatric population has access to suitably adapted, tested and labelled medicines is outweighed by the lack of commercial interest for pharmaceutical companies to develop medicines for use in children. Studies in children are described as being difficult to conduct, ethically challenging and expensive. The development of specific formulations adapted for use in children presents an additional expense. Furthermore, there is little incentive to apply for the authorisation of products for use in the paediatric population when it is common practice, albeit through necessity, for health care professionals to prescribe off-label.
It is easier to find answers to the question of how to introduce effective obligations and incentives for new products or products that are still covered by patent or data protection than for off-patent products. Extensions of existing periods of patent or data protection can be used to provide incentives, and requirements to provide the results of a pediatric study program can be imposed when an application for marketing authorization is submitted.

But for older products, there is no period of protection to be extended. And the product will often be marketed mainly (sometimes only) by generics manufacturerswhich tend not to have large resources for research and development, or expertise in conducting clinical trials that go beyond the studies required to demonstrate that their product is equivalent to the innovator product. The original innovator may no longer be interested in developing the product.

Nevertheless, because many of the products used most frequently off-label or on an unlicensed basis for children are off-patent, it is important to deal with these products too. So one idea is to create a study fund to support studies on off-patent medicines, available to both commercial and non-commercial sponsors, and aimed at pediatric studies that could support the inclusion of pediatric information in the terms of a marketing authorization.

Sensitivities are high, however, over the size of such a fund, its source of financing, its management, and the way it would allocate money to sponsors. Because sorting out these problems may well take a long time, the current EU thinking is to move ahead first with a proposal on new medicines, and leave the question of older medicines until later.

An informal draft of a legislative proposal was discussed with member state experts in the EUs Pharmaceutical Committee during May, and European ministers looked briefly at the plans at their June 2 meeting. Belgium was particularly outspoken in urging rapid action at EU level to fill the voidwhat it called the precarious situation in relation to the production of medicines for children. Belgium insisted that particular attention should be given to the ethical aspects of clinical trials involving children.

An EU ad hoc expert group has been set up to study the matter further. It will hold its first meeting in July. A formal EU proposal is likely to emerge once the impact assessment has been completed, at the end of this year, or early in 2004.

Progress with rule changes
Meanwhile, the bigger picture of EU drug legislation shifted slightly at the same early June meeting of EU ministers. The EU plan to update the way the European Agency for the Evaluation of Medicinal Products operates (which has also been held up by conflicting views among EU member states) moved one step closer to becoming reality. Ministers provisionally agreed to a typical European compromise which satisfies no-one completely, but is not downright obnoxious to anyone.

The compromise covered the two most contentious points in the proposed new rulesthe scope of the EUs centralized procedure for granting marketing authorizations, and data protection.

On the centralized procedure, the initial plan to make it obligatory for all new products was watered down. It will now be obligatory only for products for human use containing a new active substance for which the therapeutic indication is the treatment of AIDS, cancer, neurodegenerative disorders, or diabetes. Everything else can still use the national procedures, and win EU-wide market access through the alternative decentralised or mutual recognition procedure.

On data protection periodsthe time during which a company would be able to protect its rights to clinical data on a product against another company using them to seek authorization for a competing productsome harmonization of divergent national practice was agreed, but less than had been planned. The deal will let generic companies apply for marketing authorization eight years after the original medicinal product was granted a marketing authorizationbut the generic could be placed on the market only after an additional period of two years, that is, 10 years in total. And for products where the centralized procedure is compulsory, the 10-year period can be extended to 11 years in the case of a new indication.

But the European pharmaceutical industry didnt like the compromise. The European Federation of Pharmaceutical Industries and Associations immediately said that EU ministers missed an important opportunity by not fully supporting the proposal to provide 10 years of regulatory data protection for all new products, across the board. It interpreted the agreement to provide a weaker level of protection for some products registered as missing the opportunity to boost the competitiveness and innovative capacity of the European pharmaceutical industry, and the research that patients need and expect.

The deal agreed to by ministers (they will have to formalize their views in October) offers some small improvement on what is already available in most of the EUs fifteen member states, by providing for an eleventh year of protection for a new indication on an existing product. It will, however, improve the situation in the handful of current member states which currently offer only six years exclusivity, and in the ten new member statesmainly from the former Soviet blocthat will join the EU in May 2004.

References1. William Shakespeare, As You Like It, 2.7.