EU Scorecard on Medicines for Children

September 1, 2008

Applied Clinical Trials

Applied Clinical Trials, Applied Clinical Trials-09-01-2008, Volume 0, Issue 0

Keeping score of Europe's one-year-old initiative to promote research for the pediatric community.

In its first full year of operation, the work of the new pediatric medicines committee at the European Medicines Agency (EMEA) in London has led to the formal approval of only 15 pediatric investigation plans (PIP), according to data recently released by the European Union.

As many readers of this column are aware, since the start of 2007 there has been a new European rule requiring all European marketing authorization applications to be accompanied by an outline of how the product is to be tested for use in children or by a compelling argument for a waiver of the obligation. Of the 233 applications the committee received in the last 12 months, 49 were requests for a full waiver for all conditions and all subsets of the pediatric population, covering some 420 indications. The committee adopted 71 opinions: one was negative, 39 were approvals of PIPs, and 31 were approvals of full waivers.

Peter O'Donnell

The committee's opinions are then given formal status as decisions of the EMEA in London—a process that takes additional time. So by a coincidence, in formal terms, at present there has been approval of 15 PIPs and 15 waivers.

On July 28th the first inventory was published of the results so far of the EU scheme to boost research for medicines for children. It also lists the rewards being offered at the EU and national level, over and above the six-month extension to patent protection. The specially favorable conditions for orphan medicines (which include two additional years of market exclusivity) attracted around 40 applications, and three-quarters of these provided a full PIP with no request for any waiver.

Forty-plus schemes

The inventory reveals that by July of this year there were more than 40 different schemes in operation in Europe to promote research into medicines for children. At the EU level, they include—in addition to the operation of the pediatric medicine regulation—a range of EU-funded research programs. Among the most advanced are a project for selecting and validating drug targets from the human kinome for high-risk pediatric cancers, the development of a European embryonal tumor pipeline, work on chimeral T cells for the treatment of pediatric cancers, and a task force for drug development for the young population.

Funding has also been granted to a project entitled Relating Expectations and needs to the Participation and Empowerment of Children in Clinical Trials. The EU is also finalizing a proposal to promote childhood immunization, which will urge member countries to step up efforts to achieve high childhood vaccination coverage for priority vaccine-preventable diseases.

There are also numerous national schemes in the member states to promote research into children's medicines. Austria offers financial grants and scholarships and, along with Bulgaria, tax breaks. In the Czech Republic, the ministry of health is preparing a program for 2009–2011 that includes pharmacological and pediatric research, focused on improvement of health care for young people, new therapeutic procedures, and other contributions in the field of pediatric health care provision.

Breaking it Down: PIPs and Waivers

In France, experts from the National Medicines Agency provide scientific advice free of charge for the development of potential pediatric medicines, and the National Health Agency is creating networks of pediatric investigators. The Agency has also introduced controlled systems for access to medicines without market authorization in France. Preauthorization access can be arranged for patients with serious or rare diseases (a quarter of which are children, says the Agency).

Steps are also underway to allow access to medicines authorized elsewhere in the EU but not in France. And if a suitable proprietary medicinal product is not available, hospital pharmacies are authorized to produce their own preparations, which are then declared to the Agency—and nearly half of all medicinal preparations are for pediatric use.

Italy has established a pediatric working group to coordinate all issues related to pediatric drugs. Spain has made a priority of pediatric research in its latest support plan for biomedical research. And in the UK, a research network for medicines for children has been set up to improve the coordination, speed, and quality of randomized controlled trials and other well-designed studies of medicines for children and adolescents.

The situation in Poland is unclear. The country's new law on clinical trials is still under preparation, to replace some 13 separate legal acts and regulations. But it is not possible to say when the legislative process will come to an end. The draft currently contains a section relating to protection of particular groups of clinical trial participants, which is aimed at covering, among others, trials involving persons under age. It also envisages additional conditions for clinical trials and content of the trial protocol, and arrangements where there is lack of parental consent or for consent of under age participants.

The work evolves

Meanwhile, the latest news from the EU's pediatric medicines committee in London, which met right at the end of July, provides further demonstration of how it is shaping up to its new task. Positive opinions were adopted on PIPs for four more medicines: Boehringer Ingelheim's dabigatran etexilate and Bayer's recombinant thrombin alfa, both in hematology and hemostaseology; and Boehringer Ingelheim's pramipexole dihydrochloride monohydrate and Valeant's retigabine, both in neurology.

The committee also adopted negative opinions on PIPs for MSD's ezetimibe and simvastatin, and nicotinic acid, simvastatin and laropiprant, both in endocrinology and metabolism, but then went on to provide—on its own initiative—positive opinions on full waivers for these medicines in all subsets of the pediatric population on the grounds that they do not represent a significant therapeutic benefit over existing treatments. It was also agreed that the obligation to submit data obtained through clinical studies with children be waived in all subsets of the pediatric population for Janssen-Cilag's bortezomib in oncology.

The pediatric committee meeting also endorsed plans for instant enforcement of the new rule, bringing some additional clarity to the clearance procedures. As of July 26, 2008, companies submitting an application for a marketing authorization for a medicine have to provide the results of studies in children conducted in accordance with a fully and finally approved PIP that has been endorsed by the Medicines Agency decision, unless it can show it has received a formal confirmation of a waiver or deferral. This will apply from January 26, 2009, for medicines that are already authorized and for which a company is submitting an application for an extension of indication.

The pediatric committee's role will be to assess and formulate an opinion on how far the application for marketing authorization has complied with the agreed pediatric investigation plan—that is to say, it will assess whether all measures agreed in a PIP have been carried out in accordance with the terms of its formal approval. If compliance is inadequate, not only may the application run into approval problems, but the product will also fail to qualify for the rewards and incentives provided for by the scheme.

Transatlantic cooperation

As part of the efforts to create a framework for global pediatric development plans, the EU pediatric committee meeting was attended by a representative of the U.S. FDA. This relatively unusual occurrence is likely to become more frequent. So-called "principles of interaction" have been established between the London Agency and the FDA in relation to pediatric therapeutics, and these allow EU staff to attend meetings of the FDA's pediatric implementation team, and FDA staff to attend EU pediatric committee meetings. The aim is to help regulators from both agencies observe operational activities, to optimize mechanisms and timing of information exchanges, and overall to avoid exposing children to unnecessary clinical trials.

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

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