What Shall We Do About the Children?

The EU offers up market advantages in exchange for pediatric trials

This is a vulnerable group with developmental, physiological and psychological differences from adults, which makes age and development-related research particularly important." That is the underlying rationale for the European Union's continuing efforts to get its pediatric medicines proposal right.

So the EU has been talking to everyone who will listen in a bid to get it right. Still wounded from the hostility to its clinical trials rules that came into effect in May, it is anxious to head off more criticism about how it legislates. The EU has been conducting a major consultation exercise, promising to take due account of the contributions it receives.

All of which is a little curious, since the EU has already made its proposal-and held a major consultation exercise before that, too. The excuse for the new round of reflection is that the EU "wishes to further consult stakeholders." The previous consultation, back in 2002, covered only "the key elements to be included," it now says. And while that earlier feedback was "carefully considered" and even "shaped the draft legislative proposal," it wasn't enough. As part of the EU's complex lawmaking procedures, the whole thing is now subject to what the Brussels machine calls an "extended impact assessment."

Believe it or not, this complicated procedure is all the consequence of a new EU strategy called the "Better Regulation Action Plan"-provoking the obvious reflection that it might have been a better Better Action Plan if the consultation had all taken place at the same time. It would certainly have been a Quicker Action Plan.

The substance
So much for the procedure. As to the substance, the aims of the new rule remain the same as outlined two years ago. As the EU expresses it in its new consultation document, "to improve the health of the children of Europe by increasing the development of medicines for use in children, ensuring that medicines used to treat children are subject to high-quality research and are appropriately authorised for use in children, and, improving the information available on the use of medicines in the various paediatric populations." And, it adds, this is to be achieved "without delaying the authorisation of medicinal products for other populations."

The EU knows it has to remedy the flagrant gap between adult and child medicines. While preclinical tests and clinical trials ensure adult drugs are safe, high quality, and effective, that testing is simply not conducted for more than half the medicines used in children. It leaves nearly a quarter of Europe's population exposed-some 100 million children across the EU's 25 member states.

As the EU says in its new consultation document, "it is particularly ironic that the legislative framework that ensures the high standards of safety, quality and efficacy necessary for the authorisation of medicinal products for use in adults was initiated over 30 years ago in response to therapeutic disasters occurring in the paediatric population. Yet today children continue to be exposed to similar risks, and at the same time may miss out on therapeutic advances."

The industry's faultThe blame for this situation is laid squarely at the door of the pharmaceutical industry. "It results from the fact that frequently pharmaceutical companies do not perform the necessary research and development to adapt medicinal products to the needs of the paediatric population," the EU statement explains. "This leaves no alternative to the prescriber than to use products 'off-label' and use unauthorised products with the associated risks of inefficacy and/or adverse reactions. In addition, existing data which could provide useful and important information are frequently not made available to the health practitioner."

European practice to date is contrasted critically with what has been achieved in the United States in the consultation document. Recent U.S. pediatric studies conducted in response to U.S. legislation led to 64 labels containing new pediatric information for established medicines between July 1998 and February 2004, it points out. Two thirds of the new labels included important new dosing/pharmacokinetic, efficacy, or safety information which had an impact on the safe and effective use of the medicine in the pediatric population. "Without specific studies in the paediatric population, this important information would not be available and children would continue to suffer."

It is unlikely that there will be any substantive progress in this area in the European Union until there is a legislative system in place, the EU believes. Some EU member states have tried to increase the availability of information on the use of medicines in the pediatric population and to increase the availability of authorized medicines that are specifically adapted for use in the pediatric population. But their efforts have been largely unsuccessful. And the success of the measures taken in the United States has brought little benefit to the children of Europe. International companies seem unwilling to voluntarily submit U.S.-collected data to support the authorization of EU pediatric indications.

A balanced system needed
A balanced system combining obligations and incentives or rewards is therefore necessary to stimulate the necessary development, the EU has concluded. Although there may be ethical concerns about conducting trials in the pediatric population, this has to be balanced by the ethical concerns about giving medicines to a population in which they have not been tested. It is proposing a broad package of measures, impacting on a mix of medicines currently being developed and those already authorized, whether covered by a patent or supplementary protection certificate or not.

Extensions of the period of protection can be used to provide incentives or rewards for products still under patent, and requirements to provide the results of a pediatric study program can be imposed. This is what the EU is planning for new products and for medicines covered by a patent or a supplementary protection certificate.

Companies will have to present the result of studies in children according to an agreed pediatric investigation plan at the time of marketing authorization application, or application for a new indication, dosage form or route of administration. Some fail-safe mechanisms are built in to the requirement. A system of waivers will ensure that research in children is only conducted to meet the therapeutic needs of children. A system of deferrals will ensure that research is done only when it is safe and ethical to do so. And deferrals will also ensure that the requirement for data in children will not block or delay the authorization of medicines for other populations.

The reward will be a six-month extension of the supplementary protection certificate (the EU form of patent extension), provided there is submission of data in children-whether the results are positive or negative-and updating of the product information.

For products not covered by a patent or a supplementary protection certificate, incentives and requirements are more difficult to design. There is no period of patent protection to be extended to provide an incentive, and requirements for research and development may be unduly onerous for some manufacturers of generic products. But this is an important category, accounting for more than half of the products used most frequently off-label or on an unlicensed basis in the United States.

So the EU is proposing the incentive of data protection on any new studies on the safety, quality, and efficacy of the product in children. It will link a new type of marketing authorization, the Paediatric Use Marketing Authorisation (or "PUMA"), together with a study program to fund or partly fund research into the pediatric use of off-patent medicines (Medicines Investigation for the Children of Europe, or "MICE").

To support the new system, the EU also proposes the creation of an expert committee, the Paediatric Board, within the European Medicines Evaluation Agency, and the establishment of procedures for pediatric investigation plans and marketing authorizations. The new board will include representatives of the member states, associations of professional and patient representative organizations, and ethicists appointed by the EU. It will be complemented by free scientific advice to companies from the EMEA, a survey of the use of medicines in children in the member states, and an inventory of the therapeutic needs of children-which will form, in part, the basis for waivers from the requirement for data in children and deferrals from the implementation of studies in children.

A database will be created of agreed pediatric investigation plans and the studies conducted as a result of them, based on the database set up under the terms of the EU Clinical Trials Directive. Industry will have to submit pre-existing studies relating to the use of medicines in children. And annual reports will be published on the companies that have benefited or failed to comply with the measures in the paediatric legislation.Companies will be required to outline pharmacovigilance plans as part of a marketing authorization application, and regulators will be entitled to require a risk management system or post-authorization data collection for a particular product associated with a safety concern.

Market access will be eased by allowing products to use the EU's centralized procedure for applications, and enforced by a requirement for authorized products newly granted a pediatric indication to market the product within twelve months.

Additional stimulus and incentive for research will be delivered through new funding for studies and clinical trials into the pediatric use of medicines not covered by a patent or a supplementary protection certificate. The creation of the funding and its operation will be included in separate legislation.

The need for action is unquestioned-because "problems resulting from the absence of suitably adapted medicines include inadequate dosing information leading to increased risks of adverse reactions including death, ineffective treatment through under-dosing, non-availability to children of therapeutic advances, as well as extemporaneous formulations for children which may be poorly or inconsistently bioavailable." It remains to be seen how fast the EU will act-and how far its complex legislative procedures will improve the action it takes.