Dose finding in pediatric patients.
It is generally agreed that satisfactory safety and effectiveness of pharmaceutical products for children and adolescents have not yet been established. This applies in particular to anti-cancer drugs and even to those having successfully been used for many years in multidrug chemotherapy protocols for childhood cancer. For example, nephroblastoma or Wilms' tumor is one of the typical and frequent forms of childhood cancer occurring at a median age of about 3 years. Standard therapy for Wilms' tumor is the combination of vincristine and actinomycin D; survival is about 85%. For actinomycin D, the summary of product characteristics states that one contraindication is children aged below 6-12 months. If this would be considered and respected it would mean that a substantial proportion of children with Wilms' tumor would not be treated and thus a proven curative therapy would be withheld. The current situation in pediatrics is that off-label use has become a common practice: in private practice about 20% of prescriptions are off-label, in children's hospitals approximately 40%-50% with 50%-70% in pediatric oncology and more than 90% in neonatology (Conroy et al. 1999, 2000, 2003; Turner et al. 1996, 1998; McIntyre et al. 2000). These conditions are more or less tolerated by the authorities although they are beyond legality. The reason is that appropriate clinical trials like those in adults have not been conducted in children and drugs have therefore not been licensed.