Europe's Pediatric Rules in Force—At Last

It's taken a long time, but the much-discussed European Union regulation on medicinal products for pediatric use has finally come into force. It's almost with a sense of weariness that I report this, since I have the feeling I've wearied readers of this column with repeated accounts of the successive stages of its long gestation.

Peter O'Donnell

However, the culmination of this process is far more important than any minor quibbles about how long it's taken the European legislative machine to get here. The new regime should be good for children and good for drug development. It should also provide plenty of additional work for the clinical trials community.

The new regulation certainly received an enthusiastic welcome from the European pharmaceutical industry. "More medicines designed especially for children will soon be available across Europe," said the European Federation of Pharmaceutical Industries and Associations (EFPIA). "It will undoubtedly change Europe's research and development environment."

Throughout the long debates—going back well before 2004—EFPIA has consistently argued for scientific and regulatory measures to encourage the development and authorization of medicines assessed for use in children; for incentives to support pediatric investigations into new and older products; and for the creation of a pediatric R&D infrastructure in Europe.

According to Brian Ager, EFPIA director general, "the final text overall maintains a balanced approach between obligations and incentive measures. We sincerely hope these measures will contribute to Europe reclaiming a central role in innovative drug development as quickly and efficiently as possible, with a view to meeting the needs of the pediatric patient population."

More work for authorities too

The new regulation features prominently in the 2007 agenda of the European Medicines Agency. It is one of the factors that will lead to "a considerably increased volume of activity," according to its just-published work program for the year.¹

Its work program has also been heavily influenced by the entry into force in January 2007 of the legislation on pediatric medicines. This is an important new mandate for the agency, giving it a significant role in stimulating the availability of safe and effective medicines for children, and is likely to lead to a 30% increase over 2006 in its provision of scientific advice to applicants.

The agency will have to set up a new pediatric committee in the second quarter of 2007 to deliver opinions and decisions on pediatric investigation plans (and waivers where justified), and will have to provide information on pediatric clinical trials. Although the agency anticipates around 50 requests in 2007 for scientific advice relating to pediatric medicines, it expects overall some 400 requests or applications relating to pediatric activities (such as pediatric investigation plans, waivers, and scientific advice).

The new committee will assess, agree, and verify compliance with pediatric investigation plans and waivers. An agreed pediatric investigation plan may lead to information on the pediatric use of medicines being included in a centralized or national marketing authorization for new medicines, and in a pediatric-use marketing authorization for off-patent products.

New EU Member State Woes for GSK & AZ

The agency will also begin the gradual establishment of a European network for pediatric research, and in liaison with the European Commission and the 27 EU member states, it will start delivering guidelines for transparency of the pediatric clinical trials database. Work will also commence in the area of pediatric pharmacovigilance. A number of related guidelines will be implemented, and expert fora for the investigation of new sources and methods for intensive monitoring of the pediatric use of medicines will be established.

Other agency tasks for 2007

There are plenty of other clinical trials-related activities facing the agency this year. It expects intensified activity on evaluation and supervision of medicines, and scientific advice and protocol assistance for sponsors will remain major areas of activity, particularly to foster new innovative technologies and therapies and to improve the chances of early availability of new medicines. The agency says industry is showing greater interest in seeking early scientific advice, with a significant increase in the number of requests from year to year translating into a high workload.

In line with its declared policy of supporting innovation, the agency promises to focus in 2007 on providing special support for small- and medium-sized enterprises and contributing to pan-European initiatives for facilitating innovative research. Its efforts will particularly include continued support for the EU orphan medicines policy.

Emerging therapies and new technologies are posing new challenges too. The agency is already engaged in providing advice in early stage development of advanced therapy medicinal products—gene therapy, somatic cell-therapy, and human tissue-engineered products—as well as other new technologies that will not fall within the scope of the upcoming EU regulation on advanced therapies.

The agency plans to promote early dialogue with sponsors of potential applications for advanced therapies and emerging products and technologies, and will widen its exchanges to academia and society at large, in a bid to identify expertise, expectations, and bottlenecks relating to new treatment solutions. One of the consequences during the year will be the drafting of a "Strategic plan for new technologies."

There is a shift underway in general pharmacovigilance, too. Medicines agencies have traditionally relied on spontaneous reporting of adverse reactions, but the agency says it now wants to take this a step forward. It is planning to work with member states' authorities and academic centers on establishing networks of experts to run intensive drug-monitoring programs that will actively study the safety of targeted medicines.

Faced with a surge in responsibilities, the agency is also starting to insist on improved cost-effectiveness of its own operations, and on the need for further financing. It must be "supported by a corresponding increase in finances, human resources, and allocated national experts," says its executive director, Thomas Lönngren.

GCP and clinical assessment

The agency will carry out GCP and pharmacovigilance inspections, and organize training activities on GCP. It will also develop the cooperation between inspection and assessment functions, particularly through joint sessions with GCP inspectors and clinical assessors. It will have to continue its support for the implementation of directives on GCP.

The detailed work plans for some of the agency's working parties also indicate where they will be impinging on the world of clinical trials. The pharmacogenetics working party—which will meet five times during the year—will be contributing to the scientific advice and protocol assistance on relevant pharmacogenetics and pharmacogenomic aspects, and will hold briefing meetings with applicants in response to specific requests.

It will also be finalizing new guidance on pharmacogenetics. One paper will deal with pharmacogenetic samples, testing, and data handling. Another will cover pharmacogenetics and pharmacokinetics studies. A reflection paper will be completed on the use of genomics in clinical trials to explore treatment and genomic traits, and another will consider the agency's experience with authorization applications relating to pharmacogenomics in oncology.

The recently established biosimilar medicines working party will be developing new guidance, too, covering nonclinical and clinical issues on biosimilar medicinal products containing biotechnology-derived proteins, recombinant α-Interferons, or low molecular weight heparins. It will be working too on training on assessment of the quality, nonclinical, and clinical aspects of biosimilars.

The gene therapy working party will be contributing to the scientific advice and protocol assistance too, as well as to marketing authorization and postauthorization procedures on gene therapy and gene transfer medicinal products. It is also involved in:

• reviewing its guidance on quality, preclinical, and clinical aspects of gene transfer medicines

• preparing guidance on the scientific criteria for qualification as a gene therapy medicine, and on genetically modified cells as gene therapy medicines

• preparing a guideline on nonclinical studies prior to clinical use of gene therapy medicines and on monitoring of subjects treated with them.

Biomarkers

The burgeoning biomarkers market is also driving intensive work within the agency. A recent study by Kalorama Information² predicts the worldwide market for biomarkers in clinical trials will jump from $427 million in 2006 to more than $1 billion in 2010.

Their increasing usage in drug development and clinical trials is expected to have an enormous impact on the success and effectiveness of future therapies, says Kalorama.

The European medicines agency is currently finalizing a series of definitions to avoid the risk of confusion in this rapidly emerging new field. "The lack of consistently applied definitions to commonly used terminology raises the potential for conflicting use of terms in regulatory documentation and guidances or inconsistent interpretation by regulatory authorities, ethics committees, and sponsor companies," it says.

A guideline now in preparation provides definitions for genomic biomarkers, pharmacogenomics, pharmacogenetics, genomic data, and sample coding categories "to facilitate the integration of the discipline of pharmacogenomics and pharmaco-genetics into global drug development and approval processes."

According to the agency, the definition of what constitutes a genomic biomarker is key to understanding the definitions of pharmacogenomics and pharmacogenetics. So it sets out clearly that a genomic biomarker is "a measurable DNA or RNA characteristic that is an indicator of normal biologic processes, pathogenic processes, and/or response to therapeutic or other intervention." It is not limited to human samples, and could, for example, reflect the expression, function or regulation of a gene. It can consist of one or more DNA or RNA characteristics. And if you want to see the full text, and the other definitions, you can find them at: http://www.emea.europa.eu/pdfs/human/ich/43798606en.pdf.

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

References

1. http://eurlex.europa.eu/LexUriServ/site/en/oj/2006/l_378/l_37820061227en00010019.pdf

2. http://www.kaloramainformation.com/Biomarkers-Briefing-1059917.