No Orphans Among European Children?

Now that the European Unions scheme for promoting orphan medicines is up and running successfully, the EU is turning its attention to the treatment of diseases in children. And its plan to boost the industrys attention to developing pediatric treatments owes much to the incentive schemes the EU has used for orphansand much more to the recent U.S. thinking, too.

The EU recently set out its thinking in a consultation document,¹ which emphasizes the need for actiongiven that up to 90% of medicines administered to children have never been specifically tested for use in children.

The justification is simple, and simply expressed, Before any adult is treated with a medicine, he or she can be sure that it has been extensively tested to assure that it is safe, effective and of high quality for use in adults. The same may not be true for medicines used in children, the Commission saysadding that this is all the more striking since there are about 75 million people under 16 years old in the EU, representing a fifth (20%) of the total population.

As a result, EU medicines frequently do not include information on safe and effective use in pediatric populations. This in turn leads to the use of unauthorized medicinal products and/or medicines used off-label, outside their approved terms, and may result in significant risks, including lack of efficacy and/or unexpected adverse effects, even death, the consultation document points out.

Pressure has been growing in Europe over recent years to do something about this situation. The issue has been raised by regulators, individual member states, members of the European Parliament, pediatricians, and parents, and, in December 2000, the European Unions Council of Ministersthe EUs top decision-making bodyasked the European Commission to take some action.

Diagnosis
After intense discussion with the 15 EU member states in November 2001, the Commission made what it calls one of the first steps. It acknowledges the obvious in its diagnosis of the problempharmaceutical companies have traditionally been reluctant to invest in developing specific treatments or adapting existing medicines to meet the needs of the pediatric population, mainly because the market is small and therefore of lower priority to them. This is compounded by the fact that the risks associated with pediatric treatments are generally higherincluding therefore the need for long-term follow-up of adverse effects. Specific clinical studies may be difficult to design and as a result may be costly, and the revenue from the pediatric development of the products is not perceived as justifying the cost of the clinical trials. Market forces are inadequate to stimulate the necessary studies in children, it remarks.

As far back as 1997 a broad discussion of the issue at the European Agency for the Evaluation of Medicinal Products concluded that a system of incentives was needed. Despite some legal provision for the conduct of trials in children, there is currently no legal provision for obliging these studies to be performed if the company does not present the product for use in the pediatric population, even if there is a clear therapeutic need for the product.

Prescription
The EU has come up with a long list of possible treatments in this consultation document. To encourage the performance of appropriate studies for medicinal products for which protection of intellectual property exists, it proposes an additional period of market exclusivity as a reward for submitting one or more validated clinical studies on children of one or more age groups. This period of market exclusivity would apply at the end of the existing period of patent or Supplementary Protection Certificate protection.

Regulatory authorities would be required not to accept applications for generic marketing authorizations until this additional period had elapsed. A mechanism similar to the written request system in the United States could be developed in order to ensure that the studies performed were both useful and appropriate. One possibility would be to ask companies to submit a development plan, which would be assessed by an EU expert group before agreeing that eligibility for the clinical studies be considered within the new legal provisions. A mechanism to predefine criteria in order to avoid unnecessary studies could also be put in place.

For already marketed medicinal products where no intellectual property exists, the EU proposes to encourage studies by introducing a period of data protection for a marketing authorization with a pediatric indication through the creation of a new type of kid marketing authorization. The protection would be valid for the active substance and indication combination. In order to help this work in practice, it would be possible to create a new kind of marketing authorization, possibly with a specific prefix or suffix, such as Kid-drug or Ped-drug. This would make it easier to distinguish it from an existing marketing authorization, thus helping to ensure that the new pediatric data was protected. It would also allow companies that were not the originator to exploit known medicinal products and develop specific formulations supported by specific studies. Only the pediatric indication would benefit from the data protection provisions.

Studies could also be encouraged through the creation of a fund which could be used to fund clinical or nonclinical pediatric research. A significant source of income is required in an area where there is little other incentive to do this work. The Commission estimates that in Europe, based on an average cost of E5 million ($5.5 million) per trial, 20 studies could be performed annually for about E100 million. As to where the money might come from, the Commission suggests using some of the proceeds from the additional profits made by the extension of the intellectual property or market exclusivity provisions to create a fund, which could then be used for further studies on already marketed products. In principle, it says, this fund could then be used to contract out certain research projects. There may also, it suggests, be ways of switching other EU or national sources of research funding, through already-established programs, into pediatric studies.

Sticks as well as carrots
The EU also considers coercion alongside incentives. It suggestsclaiming U.S. precedentroutinely requiring studies in pediatric populations as part of the marketing authorization application requirements. EU applicants would be required to submit the results of studies performed as a requirement for validation. Pediatric applications would be screened by a European expert group, to determine whether or not the studies were acceptable in principle (that is, whether they corresponded to predefined criteria). The assessment of these studies would then form part of the normal assessment of the marketing authorization. A waiver might be available in cases where there is no therapeutic need in pediatric populations (such as for Alzheimers disease or certain heart conditions), but it would be the responsibility of the applicant to justify a waiver. In certain cases it might also be possible to defer the completion of the studies until after the application for the adult population had been submitted, on the basis of a development plan and justification provided by the applicant.

Other mechanisms, such as the creation of a dedicated European expert group, and a European network of pediatricians with specific competence in the oversight of appropriate trials in children, are examined. So too are questions of how information could circulate better, as well as the need for ensuring that the ethical standards in the EU directive on Good Clinical Practices are complied with in trials on children. The consultation document insists on the need to ensure that in any trial involving children, appropriate informed consent procedures are developed and used, the wishes of the child are respected, measures to minimize pain and distress are taken, and the responsible ethics committee has involved specific expertise in the field of pediatrics.

Industry response
The European pharmaceutical industry has already given its preliminary response, welcoming the concept but questioning the effectiveness of the mechanisms proposed.According to the European Federation of Pharmaceutical Industries and Associations (EFPIA), the lack of a regulatory framework and incentives for pediatric research has meant that European children often have not had the benefit of appropriately researched medicines, leading to unnecessary and sometimes dangerous risks in prescribing medicines for children, and to the weakening of pediatric research and infrastructure in Europe. It points out that the EU initiative lags behind United States action by many years.

For the industry, the key consideration is to offer new incentives for research. So for a product for which intellectual property protection exists, EFPIA says an extra market exclusivity period of at least 12 months should be granted. But a clear definition is needed for the nature of the market exclusivity and the mechanisms for its enforcement, to ensure that the innovator is the sole entity permitted to put on the market a product containing the active substance in question. Prohibiting regulatory authorities from accepting applications for generic marketing authorizations until the additional exclusivity period has elapsedas proposed by the Commissionmay be insufficiently effective, so specific measures allowing the innovator to seek redress, including injunctive relief, should a marketing authorization be inappropriately granted are also required, it says. Alternatively, the innovator could be granted a sui generis right extending existing protection.

Products for which no intellectual property protection exists could be covered by a period of market exclusivity attached to a new type of child-related marketing authorization, as the Commission has suggested, concedes EFPIA. But unless the legislation makes clear that the protection will be on the same level as that presently granted to orphan medicinal products (with market exclusivity of 10 years), the mechanism will not be sufficiently robust to offer a real incentive, particularly for smaller firms, it says.

The industry backs the Commissions idea of a fund financed by EU and national budgets, but says it would need to be comparable to the $200 million allocated by the U.S. government, and should not be supplemented by taxes or clawbacks on the pediatric incentives, because that would be counterproductive.

Where the industry diverges clearly from the current Commission thinking is on eligibility conditions for incentives. Granting incentives for products already covered by patent or other protection should not be dependent on the final outcome of the pediatric development program. And there should be no blanket requirement to present results of pediatric studies when seeking a marketing authorization for a new medicine, says EFPIA. This could slow up the availability of valuable new medicines for adults. The submission of pediatric data at the time of the first marketing authorization application cannot realistically be the norm, with the exception of certain diseases that occur primarily or commonly in the pediatric population, it says. In most cases, it would be more appropriate to require that a development plan for pediatric studies should be submitted along with the marketing authorization application.

Industry is also cautious over the Commission plans to establish a database of ongoing EU clinical trials for children, because it fears undue disclosure of confidential development plans rather than results of studies. And it insists that any EU initiative to boost development and testing of medicines for children must be accompanied by appropriate funding, to allow sufficient funds for the additional specialist work that EU regulatory authorities will have to take on board.

When the consultation period ends, the real work will begin, and could lead to a formal legislative proposal before the end of this year. But sinceas the EU recognizesmost of the solution lies in the hands of the industry, unless the new law offers something that the industry wants, it wont make much difference.

References
1. European Commission, Better Medicines for Children: Proposed regulatory actions on paediatric medicinal products (European Commission, Brussels, Belgium, 2002).

SIDEBAR: Recommendations from the European Forum for Good Clinical Practice

As Peter ODonnell points out, much of the discussion in Europe has recently focused on the European Commissions consultation document Better medicines for children. This paper is intended to provide a first framework for the consideration of legislative action that would improve the labeling of medicines for use in children.

Following extensive debate among legislators, regulators, industry, pediatricians, patient organizations, and others involved in health care for children, the European Forum for Good Clinical Practice offered the following advice on the consultation paper:

1. A robust ethical framework for pediatric research in Europe needs to be created, including guidance for informed consent, ethical review, recruitment of subjects, and safety and oversight.
2. A robust pediatric clinical study infrastructure in Europe needs to be created. As a result of reluctance to perform such studies up to now, there is a serious shortage of trained and experienced people and centers of excellence.
3. Greater cooperation should be stimulated between public sector research and private sector research in the area of pediatrics, in the interest of developing a European dimension to improving medicines for children.
4. A clear framework should be developed for assembling international data and information regarding pediatric trials and medicines in order to ensure that unnecessary trials are not carried out in Europe and that European pediatricians have the benefit of up-to-date and comprehensive information regarding medicinal products for their populations, wherever in the world that information has been generated.
5. A greater public dialogue is required in Europe regarding the benefits and risks of pediatric research for individual children participating in research as well as for public health in general.

Based on the feedback from the consultation document, the European Commission expects to prepare draft legislation on pediatric medicinal development by autumn 2002. This legislation is considered by many to be pressing in order to create the conditions needed to improve medicines for children. However, already in the lead up to the legislation, over the past year nearly all parties in Europe have come together to support legal and regulatory framework for improving child health, especially regarding the labeling of medicines.

Even further, representatives of the FDA, PhRMA, and U.S. pediatricians attended the EFGCP/CESP A European Conference on Clinical Research in Children: Ethical, Scientific, and Regulatory Considerations in January 2002. Most recently this was reciprocated by the participation of European Commission and EMEA experts at an FDA Pediatric Advisory Subcommittee Meeting in June 2002.

If we can strengthen approaches between sectors while pooling resources across countries and regions, then children should be the final beneficiaries.

Francis P. Crawley, Secretary General, European Forum for Good Clinical Practice (EFGCP), fpc@efgcp.org