среда, 19 сентября 2012 г.

Preparing for Europe's Pediatric Rules - Applied Clinical Trials

After a long and winding journey, now the real work begins on the EU Regulation for all those involved.

Every parent knows the feeling. You've been dealing with the kids for so long that when they finally grow up you think: 'That's good. It was great fun, but now at last they've left home.' But they haven't. They come back - to borrow the car, to store some furniture, to bring some washing, to hang out with friends or just to get a good meal.

The clinical trials community in Europe is getting the same sensation with the pediatric medicines regulation [Regulation (EC) No 1901/2006 on medicinal products for pediatric use, http://ec.europa.eu/enterprise/ pharmaceuticals/eudralex/vol-1/ reg_2006_1901/reg_2006_1901_en.pdf.] which came into force at the start of this year. Everyone thought the real work - including its new requirements on clinical trials for children - was years ago, as the regulation wound its slow way through consultation, legislation, implementation. But it wasn't. It's still here. And it's still calling for attention. So here's the latest snapshot.

The new pediatric committee at the European Medicines Agency held its first meeting in early July, and reviewed the scientific and procedural aspects of assessing the pediatric investigation plans that the new rules make obligatory. It also looked at the strategy for setting up an EU-wide pediatric-research network, and at how to conduct a survey of existing uses of medicinal products in the pediatric population in the EU.

The committee is assembling some of the best scientific expertise available in the EU in areas relating to pediatric medicinal products - pharmaceutical development, pediatric medicine, general practice, pediatric pharmacy, pediatric pharmacology, pediatric research, pharmacovigilance, ethics, and public health. And its main responsibility will be to provide opinions on the development of medicines for use in children.

The pediatric committee is not responsible for marketing authorization applications for medicinal products for pediatric use. This remains the responsibility of the European Medicines Agency, although the Agency's Committee for Medicinal Products for Human Use may request an opinion on the quality, safety, and efficacy of a medicinal product for use in the pediatric population if the relevant data have been generated in accordance with an agreed pediatric investigation plan.

For the moment, the committee is chaired by Daniel Brasseur, pending the election of a chair at its September 2007 meeting. He was chair of the committee's predecessor, the Agency's pediatric working party, which met for the last time at the end of May after six years of operations as a temporary expert group. During this time, the working party laid much of the groundwork for the pediatric regulation and contributed to the development of pediatric medicines. It identified and regularly published pediatric needs across many therapeutic areas and provided guidance on development and supervision of pediatric medicines, including on formulations of choice, pharmacovigilance for medicines, pharmacokinetics in the development of medicinal products, and investigating medicines in the neonatal population. It also established the priority list of off-patent medicines for studies in children, which will be funded through the EU's new research program.

More members needed

The membership of the committee is not yet complete. The Agency has just asked for expressions of interest from people who wish to be appointed to it to represent health professionals and patient associations. The regulation requires six such members - and six alternates - to be appointed by the European Commission, in consultation with the European Parliament. They will be expected to attend the monthly committee meetings in London.

The rest of the committee consists of five members and five alternates drawn from the Agency's Committee for Medicinal Products for Human Use, and one member and one alternate appointed by each member state not represented by the members appointed from the Committee for Medicinal Products for Human Use.

As from July 1, the Agency has to be formally notified two months in advance of the intention to submit an application for a pediatric investigation plan (or a request for waiver or deferral), and it has just published guidance on the practical aspects [available at http://www.emea. europa.eu/pdfs/human/paediatrics/ practical_aspects.pdf]. The application for the pediatric investigation plan itself should be submitted in line with the meeting timetable of the committee. The Agency will issue a letter validating the application and indicate the name of the rapporteur allocated to the file. The company should immediately send identical sets of the final application to the appointed rapporteur and to each of the pediatric committee members.

Pediatric pharmacovigilance

The Agency has also just published an overview of comments it received on its draft guideline on conduct of pharmacovigilance for medicines used by the pediatric population. The main reservations expressed were that 'much of the guideline refers to new or evolving concepts with which there is limited experience' and 'the document is limited in its provision of details that pharmaceutical firms can use in routine pharmacovigilance planning.' The specific difficulties of monitoring pharmacovigilance in off-label use were highlighted and clarifications about the roles and responsibilities of pharmaceutical companies regarding the implementation of the guideline were considered important.

Specific clarification was requested about responsibilities in long-term pharmacovigilance - particularly on the maintenance of registries and follow-up that continues beyond the patent expiry, as well as regarding the generic manufacturer's responsibilities. But the Agency chose not to incorporate the suggestion on the grounds that long-term pharmacovigilance commitments 'may be part of a pediatric investigation plan or part of the condition of a marketing authorization. It would not be appropriate for this guideline to pre-empt either of those situations or to encroach on primary legislation,' it said.

Similarly, the Agency was dismissive of a suggestion that since 'it is no longer affordable or sensible to collect data until a long-term or growth adverse drug reaction (ADR) is suspected, it is paramount to make use of suitable networks and databases or record linkage systems which collect the appropriate routine information.' The Agency responded drily: 'There are many ways of exploring delayed ADRs. All options are to be kept open.'

To the comment that, 'For clinical trials in children it may be worthwhile to expand the definition of expeditable reporting to certain events depending on the type of clinical trial,' the Agency replied: 'Not incorporated. Firstly, it would be confusing to have different definitions of expedited reporting for different age groups. Secondly, this is outside current legal provisions.' And when clarifications were requested regarding the reporting requirements of organizations involved in clinical trials, the Agency declined to take account of the comment, observing merely: 'Reporting requirements in clinical trials are set out in the clinical trials directive and its implementing texts.'

Europe and beyond

The subject is mesmerizing Europe this year. The children's medicines working party of the European Forum for Good Clinical Practice is holding a conference in October on first European experiences with the regulation. As it points out, 10 years after the first U.S. pediatric legislation, the EU is now the second major region with a legislation aimed at strengthening pediatric pharmaceutical research to improve children's health, as well as to offer better armamentariums to the global pediatric clinical community.

Meanwhile, Canada introduced its own pediatric legislation in 2006, and other countries and regions are considering comparable moves. And the U.S. pediatric legislation - which many Europeans see as highly successful - is currently being renewed before its expiry date in September.

[Author Affiliation]

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