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• Introduction
• Clinical Back...
• Drug Developm...
• Current effor...
• References

Introduction

Childhood cancers are rare, accounting for approximately 1800 patients under 15 years of age per year in Germany [1]. They show different biological characteristics, some of which are specific to children and do not compare to adult carcinomas. Most of the cytostatic drugs required for treatment have not been approved for paediatric use, which could present problems. Childhood is in itself a risk factor for the development of drug toxicities due to growth, development of drug metabolism and clearance as well as functional organ development. The need to extend drug labelling to include paediatric indications and information on dosage and pharmacokinetics for paediatric use, to protect the safety of children with cancer, is apparent [2].

Clinical Background

Cure rates exceeding 90% for some tumours and about 70% overall have become possible today [1].This has been achievedover the last 3 decades-, by paediatric institutions who joined efforts in organising multicenter clinical trials within the framework of the German Society of Pediatric Oncology and Hematology (GPOH) together with national paediatric co-operative study groups. Standard treatments employing surgery, radiotherapy, and chemotherapy have been established. While cure rates and survival curves have levelled off over the last 15 years, the need for systematic clinical trials to continually improve the quality of life by modifications and monitoring of established treatment regimens persists. Moreover, although the quality of care is high, children have generally been treated off-label. Progress in extending drug labelling by the pharmaceutical industry has been slow due to a wide spectrum of reasons, including ethical, methodological and economical questions [2].

Drug Development

Screening and development of potentially effective new drugs in the treatment of paediatric cancers is essential. Unfortunately, the ongoing oncology screening programs of the NCI and the EORTC dedicated to the search for new cytostatics fail to include paediatric tumour entities. Most of the findings on the activity of new cytostatics in paediatric cancers are based on scientific data generated by drug sensitivity testing panels of labs within the GPOH and from other international paediatric research groups. Accordingly, phase I trials which include dose-finding, pharmacological and pharmacokinetic investigations have to be performed. The usual starting dose in children corresponds to 80% of the adult MTD [3]. Normally, even phase I trials in children should include a chance of therapeutic benefit for the individual [4]. These investigations should be carefully planned to involve methods of minimal burden to the child, blood sampling should be reduced to a minimum and patient numbers should be limited by using data gained from population pharmacokinetics [5]. Subsequent phase II trials are to establish efficacy while single drug testing is not essential. Phase III trials are to define the standard of care, which in Germany is usually done in nation-wide trials.

Current efforts

The American FDA has made continual efforts to encourage and facilitate paediatric submissions. The Paediatric Rule of 1998 and the Best Pharmaceuticals for Children Act of 2002 have provided flexibility (use of adult efficacy data) and financial incentive (six month extension of patent) to manufacturers to perform clinical trials in children. In Europe, the "Note for guidance on clinical investigation of medicinal products in the paediatric population" (ICH topic E11) was approved by EMEA and came into operation in January 2001. In addition, the European Parliament published Directive 2001/20/EC in April 2001 which standardises clinical trials in children in Europe and will be implemented into German Drug Law by May 2004. This should encourage and facilitate paediatric medicinal product development in Europe. Other incentives for drug development and clinical trials have been supported by BMBF, which established a national paediatric competence network within six Clinical Trial Coordination Centers trained to perform paediatric trials conforming to ICH-GCP.

Future objectives include submission of quality clinical data to regulatory authorities to extend paediatric product labelling and further the development of new agents for paediatric indications. Children have the right to high standards-; nevertheless, flexible interpretations of flexible guidelines are required to optimise the children`s chance to benefit and to minimise risk and burden, aims which can be achieved when interaction between pharmaceutical industry, academic and regulatory bodies is promoted.

References

1. Kaatsch P, Spix C, Michaelis J: Annual Report 2000 .

   German Childhood Cancer Registry 2002.

2. Boos J: Off label use-label off use?

   Ann Oncol 2003, 14(1):1-5. PubMed Abstract | Publisher Full Text

3. Boos J: Drug trials in pediatric oncology: a multifacetted problem.

   Int J Clin Pharmacol Ther 1998, 36(11):613-20. PubMed Abstract

4. Decoster G, Stein G, Holdener EE: Response and toxic deaths in Phase I clinical trials.

   Ann Oncol 1989, 1:175-181.

5. The European Agency for the Evaluation of Medicinal Products: ICH topic E11: Note for guidance on clinical investigation of medicinal products in the pediatric population (CPMP/ICH/2711/99 EMEA) 2001

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