How are the Children Doing?

Applied Clinical Trials

Applied Clinical Trials, Applied Clinical Trials-10-01-2012, Volume 21, Issue 10

The European Union is preparing a report on the lessons learned from its 2006 pediatric regulation.

The multiple legislative progeny of the European Union include a regulation to promote testing of medicines in children—the 2006 pediatric regulation, which came into force progressively over recent years.

Peter O'Donnell

As with all good parents, the European Union is interested in how its children turn out, so it is now preparing a report on experience acquired and lessons learned from the regulation. As with all wise parents, it is taking on board views from outside the family, too—so anyone who wishes can contribute to the reflection, until the end of November. Since the subject is of obvious interest to readers of this journal, here is a snapshot of how the European Union views the issues—and a link to the consultation paper in full (http://ec.europa.eu/health/files/pediatric s/2012-09_publicconsultation_en.pdf).

Pediatric development

The first question that the consultation document asks is whether the regulation has paved the way for pediatric development, and changed the culture so that this is now an integral part of the overall product development of medicines in the European Union.

In support of its contention, it observes that before the regulation existed, many pharmaceutical companies considered the adult population as their key market, and they sidelined or simply ignored research into the potential use of a product in the pediatric population. Now that the regulation obliges companies to screen every new adult product for potential pediatric use too, the situation has been turned around, it suggests, citing unspecified feedback from companies. The requirement to develop and discuss a pediatric investigation plan with the European Medicines Agency's pediatric committee makes companies think early on about pediatric use, so as to avoid any delays in general product development, it says.

Research culture

At the same time, the consultation document offers a presumption that there are limits to how much the industry's research culture can be changed by the regulation. Most research is aimed at medicines for the adult population, primarily targeting adult conditions where there is a perceived need or market, it remarks. So the regulation can ensure that these future products are screened for their potential use in children, but it cannot guarantee that products become swiftly available in all pediatric conditions. "Rather, progress in terms of authorized products for use in children depends to a considerable extent on a company's product strategy with respect to the adult population"—which is, it suggests, "perfectly normal, as medicinal development is company-driven."

Pursuing its approach of inviting a response to a specific question, or a comment on specific presumption, it also asks about how far regulation has delivered in terms of increased products that have been researched, developed and authorized for use in children—and how far it has decreased off-label use in the pediatric population. On this idea too, it adds its own realistic view. Although the regulation has set up processes, it may be too early to assess the results.

The regulation obliges companies to establish a pediatric investigation plan for each newly developed product or for the line extension of an already authorized product that is still under patent protection, with the aim of generating data to determine the conditions in which a product may be authorized to treat the pediatric population. Since 2008 nearly 500 pediatric investigation plans have been approved by the European Medicines Agency. But until now, only a minority of them have been completed, due to the long development cycles of medicines.

So while the regulation has led to a certain amount of new authorizations that include pediatric indications, a comprehensive review will probably not be possible for a decade.

So far, the number of pediatric trials initiated in the European Union has not increased since the regulation was adopted, with the annual average hovering around 350. This may reflect, the consultation document suggests, an effective emerging balance between the need for data and the desirability of keeping trials in young populations to a minimum—through alternative means such as the extrapolation of efficacy, and avoiding the duplication of trials by different applicants through greater transparency about ongoing and completed trials.

PUMA: sleeping giant or pussy cat?

The consultation openly accepts that the regulation places new burdens on companies, because market forces alone had been insufficient to stimulate adequate research. Some of the most hard-headed assessments prompted by the consultation document relate to the effectiveness of the offsetting incentives to pediatric research that the regulation offers—particularly PUMAs, the new pediatric use marketing authorization introduced by the regulation.

This was designed as an incentive for research on off-patent medicines that have been authorized for adults, with a pay-off in terms of 10 years of data and market exclusivity to any product developed exclusively for use in the pediatric population.

"However, to date only one pediatric use marketing authorization has been granted. Neither industry nor academic networks have responded to this opportunity as widely as the regulation intended and aimed for," it laments. "It would seem that the incentive of data and market exclusivity does not work for those products, or at least that the market opportunities in this sector are currently considered insufficient to outweigh the inherent economic risks of pharmaceutical development," advances the document. "In terms of output, the PUMA concept is a disappointment."

It asks for suggestions as to why there has been so little uptake, and for predictions of whether PUMA will become more attractive in the coming years. For one of the other incentives —additional patent protection—it is simply too early for an assessment of the economic impact of the six-month extension of the product's supplementary protection certificate, the document suggests.

On some of the detailed provisions of the regulation, the consultation seeks to elicit views as to how far they have met their intended objective. For instance, companies can ask to defer elements of a pediatric investigation plan if there is a risk of blocking or delaying the authorization of medicine for other populations. The EU contention is that this deferral facilities has been successfully used and has prevented delays in the processing of "adult" marketing authorization applications.

If problems have occurred, it is usually because a company has been late in discussing its planned pediatric research program, says the European Union—challenging the outside world to disagree, and to provide evidence, if it exists, to the contrary.

Views are sought on whether the regulation has proved "an efficient and successful tool for gathering and compiling existing pediatric data and making it available to the competent authorities and subsequently, via databases, to the interested public." This relates to a requirement for companies to provide the authorities with studies that provide data on the safety or efficacy of authorized products in the pediatric population. Since 2008, more than 18,000 study reports on roughly 2,200 products have been submitted under this provision.

The data is assessed, and assessment reports covering more than 140 active substances have been published as a result, often accompanied by recommendations for changes to the summary of product characteristics of authorized products.

Shifting physicians' perceptions

Reducing the amount of off-label prescribing for children depends on more than having appropriate medicines available, the consultation documents suggests.

Doctors may need to change their habits too, and specific information measures may be necessary to achieve this, it speculates. It speaks of "a lack of recognition by general practitioners of the actual amount of off-label prescribing to children," and of a lack of awareness of the off-label status of the products they prescribe, as well as stronger influence of personal experience than evidence-based information.

Responders to the consultation are asked whether they believe it is necessary not only that the data on the use of a specific product in the pediatric population is assembled, but that it is then also appropriately communicated to, and used by, pediatricians in their day-to-day practice.

After analyzing the results of this consultation, the EU will present its report next year, including a detailed inventory of medicines authorized for pediatric use since its entry into force. But no assessment will be made of the economic impact of the rewards and incentives offered by the regulation, or of the estimated consequences for public health. That assessment will be the domain of a second, more comprehensive, report due in 2017.

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