Challenges in incentivizing the pharmaceutical industry to supporting pediatric oncology clinical trials

Abstract

In high-income countries cancer is the leading cause of disease-related death in children older than 1 year of age and therefore represents a significant public health burden. However, pediatric cancer represents only approximately 1% of all cancer cases in the Western world and all childhood cancers are individually rare (incidence <6/100,000 per year) [101]. Pediatric oncology is therefore of negligible significance to pharmaceutical companies, compared with the adult market. Historically, several additional noncommercial barriers have also been highlighted as possible blocks to drug development in childhood cancer: rare populations leading to slow accrual and small samples sizes for conventional trial designs, the need for suitable pediatric formulations (tablets and capsules are less appropriate than intravenous or liquid formulations), concerns for both acute and long-term safety in the developing child and anxiety over real and perceived ethical difficulties in studying new agents in this vulnerable population [1]. This has meant that pediatric oncologists have been obliged to prescribe drugs off-label as there is no suitable alternative and the dose and schedule are often empirical, based on extrapolation from adult data and historical experience of relatively safe usage, without appropriate pharmacokinetic information. To try and tackle this gridlock, the regulators on both sides of the Atlantic have tried to incentivize and mandate pediatric investigations in order to license a drug for an adult indication. The USA led the way with the Best Pharmaceutical for Children Act (initiated in 2002) [101], which issues written requests to a company with regard to pediatric development, the incentive being additional exclusivity. This voluntary process is augmented by the Pediatric Research Equity Act (initiated 2003) [102], which can mandate studies in children when the same indication exists in adults. Europe has followed with the regulation of the European Parliament on medicinal products for pediatric use (EC) 1901/2006 [103,104]. The aim of the regulation was to increase the availability of safety information on drugs in children, without undue delay in licensing of drugs for adult indications. The regulation made a Pediatric Investigation Plan (PIP) mandatory for any new drug, at the end of the Phase I trials in adults and there was an incentive of an extension of 6 months to the patent for the relevant adult indication. However, both the US and European programs have allowed waivers based on adult disease indications and have failed to recognize the potential for the effectiveness of therapy when based on biology rather than tumor classification.