Making Reality of Pediatric Rhetoric

The start of 2008 has brought new moves to make a reality out of the European Union's rhetoric on promoting genuinely pediatric medicines. Just one year into the new regime that requires companies to file special pediatric clinical trial plans with virtually all new products, the results are already starting to show through—not yet in terms of products validated for pediatric use, which will understandably take a little longer. But it is making real progress in terms of a functioning system that should, eventually, improve health care for kids, as well as providing some new challenges for the clinical trials community.

Peter O'Donnell

In line with the deadline set by the new rules, companies are now routinely submitting pediatric investigation plans—programs aimed at generating the necessary quality, safety, and efficacy data through studies in pediatric populations to support authorization of the medicine for use in children.

The work of the Agency's newly established scientific committee to review pediatric questions is now getting into full swing with regular monthly meetings. At its January 2008 meeting it adopted initial opinions on pediatric investigation plans for four products—Pfizer's Latanoprost, in ophthalmology, and three Merck Sharp and Dohme products: Losartan, in cardiology; Montelukast, in pneumology; and Caspofungin, for infectious diseases.

Waivers

For obvious reasons, not all new products are required to submit a pediatric investigation plan. Already, at the end of 2007, the Agency issued a class waiver for treatments for a long list of conditions that hardly or never occur in children—ranging from breast carcinoma, menopausal disorders, age-related macular degeneration to Alzheimer's Disease, vascular dementia, and amyotrophic lateral sclerosis.

Companies can also apply for individual exemptions from the requirement to conduct trials in children for individual products that are not on the 2007 list. At its January meeting, the Agency decided to accord a product specific waiver to Pfizer for lasofoxifene tartrate (for the treatment of osteoporosis in postmenopausal women at increased risk of fracture) on the indisputable grounds that the disease or condition for which the product is intended occurs only in adult populations.

Big Ideas in the Works for Little Ones

This is the fourth such product specific waiver to be granted, and follows Novartis Europharm's Everolimus for renal cell carcinoma and pancreatic neuroendocrine tumor (exempted on the same grounds as the Pfizer product) and AstraZeneca's Atacand Plus and Takeda's Blopress—both for essential hypertension—on the grounds the products do not represent a significant therapeutic benefit over existing treatments for pediatric patients.

Key deadlines

A number of further key deadlines were reached at the start of the year. Some of them were geared toward maximizing information available to authorities on the current status of pediatric trials. By the end of January 2008, for instance, holders of marketing authorizations were obliged to file information on all pediatric studies they had completed by the beginning of 2007, when the new legislation came into force.

There is also now an ongoing obligation on marketing authorization holders to submit details shortly after they complete any other studies they sponsor on products used in the pediatric population. And EU guidance has now been provided on the type of data that EU member states have to start collecting on existing uses of medicines in the pediatric population. This will allow them to communicate it to the Agency by January 2009 as part of the efforts being put into establishing a list of priority pediatric needs.

The Agency is also working on an updated priority list for studies into off-patent medicines to ensure that funds from a new round of EU research support will be directed into research for which there is a high need in the pediatric population.

European pediatric network

During January, the European Medicines Agency (EMEA) also agreed to a strategy for setting up the pediatric network envisaged by the new legislation. This is intended to embrace all the national and European networks or centers currently focused on pediatric studies, so as to build up competences and cooperation at the European level and to avoid duplicative studies. The aim is not only to benefit the pediatric population but also to provide a source of information and expertise for industry.

To match the legislation's overall aim of fostering high-quality ethical research on medicines to be used in children, the network intends to strengthen scientific, technical, and administrative competences in performing pediatric clinical trials; to make more efficient and profitable use of facilities; and to develop common methods of working, particularly to boost quality assurance. In addition, the network could help in patient recruitment.

Some of the tangible outcomes scheduled to emerge from the process include scientific and operational quality standards, training and education standards, scientific exchanges, and specific research on trial methodology.

To put the new European network into place rapidly, a coordinating group is to be set up within the EMEA consisting of representatives of pediatric centers and networks in Europe, patients or parents, and ethics committees, as well as academics and EU officials. It is expected to maintain strong links with other expert groups already established by the Agency on good clinical practice in clinical trials, GCP inspections, and pharmacovigilance.

An echo of the past

The start of the year has also been marked by a remarkable echo from the past. In January, the EMEA recommended the marketing of a product with an active ingredient so damaging on its first appearance a generation ago that it triggered much of the European medicines legislation that has appeared in the last 30 years. Thalidomide, which caused serious birth defects in the children of women who took it during pregnancy as an antinauseant, is now on the brink of being launched by a UK company, Pharmion, for the treatment of multiple myeloma.

The renaissance of this medicine is a compelling testimony to the increasing sophistication of clinical trials. The Agency concluded that the benefits of the product, in combination with melphalan and prednisone, outweigh its risks for the first-line treatment of multiple myeloma for patients over 65 years of age or who cannot be treated with high-dose chemotherapy. It was satisfied that clinical studies have shown that adding thalidomide to such a combination can prolong survival time by about 18 months in newly diagnosed multiple myeloma patients over 65 years of age, as compared to patients who received conventional chemotherapy.

However, because the drug is teratogenic, the Agency consulted representatives of thalidomide victims and myeloma patient groups from across the EU to develop measures that can effectively minimize the risk of fetal exposure. It has approved a risk management plan that includes actions intended to prevent pregnancies in women being treated with thalidomide and prevent exposure of unborn children to the medicine. For example, all women of child-bearing age who are treated with it must undergo pregnancy tests before, during, and after treatment, in addition to using selected and effective contraception.

Treatment will be initiated and monitored only by a doctor who has experience in the treatment of multiple myeloma, and a clear warning will be printed on packs indicating that the product results in birth defects and fetal death. In addition, prior to launch in each member state, the company will provide health care professionals and patients with educational materials about the treatment-related risks and the precautions required to ensure safe use.

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