Stimulation programs for pediatric drug research – do children really benefit?

The introduction of the pediatric exclusivity laws in the USA has led to pediatric drug trials for 135 drugs tested in the past eight years. Over 300 studies were performed with over 40,000 pediatric patients participating. Based on these data, the FDA claims “the pediatric exclusivity provision has done more to generate clinical studies and useful prescribing information for the pediatric population than any other regulatory or legislative process to date” [20]. The EU Commission and other policy makers see a rapid adaptation of similar legislation in Europe essential to boost pediatric drug research in the EU as soon as possible [1, 3, 19]. Although it is true that more pediatric studies have been done, we question the content of the research.

A major discrepancy is apparent between the drug prescription pattern in children and the drugs granted pediatric exclusivity. The majority of drugs granted pediatric exclusivity are rarely used by children, and drugs that are frequently used by children are underrepresented in the pediatric studies to obtain exclusivity. This difference is not accounted for by the licensing status of the used drugs. For instance, in general practice, 37% of the prescriptions of respiratory drugs are still used in an unlicensed or off-label manner [27]. This suggests that the pediatric studies did not address the real needs in pediatric drug development. Whilst the pediatric exclusivity scheme has stimulated pediatric research quantitatively, the nature of the scheme has led to priorities for the type of research that are largely driven by the adult market for medicines rather than by the needs of the pediatric population. An important built-in motive in the stimulation program for performing pediatric studies is the financial benefit gained from the exclusivity provision. The drugs granted pediatric exclusivity include 5 out of the “Top 10” prescription drugs with the highest sales figures in North America in 2005: atorvastatin (Lipitor), simvastatin (Zocor), omeprazole (Nexium), lansoprazol (Prevacid), and sertraline (Zoloft). Sales of these 5 drugs amounted to $24.1 billion US in 2005 [9]. Extension of the SPC on the basis of pediatric exclusivity has also been granted to other adult best-selling drugs, such as pravastatine, enalapril, metformin, amlodipine, paroxetine, fluoxetine, and rofecoxib (currently withdrawn). It is thus clear that the patent extension has an enormous financial benefit for the pharmaceutical companies, which easily outweighs the cost of the average pediatric trial [1]. This is not only the case for best-selling drugs but also for drugs with a smaller market share. A Tufts University report indicates that an estimated $35 million US in undiscounted profits per drug can be earned by obtaining pediatric exclusivity based on median 2004 sales for all pediatric exclusivity drugs after accounting for costs and market protection extensions [29]. Although the increased profit was intended by the legislator, we doubt if the other intention, which aimed at providing data to reduce the volume of drugs taken by children that are off-label or unlicensed, has also been met.

Our approach to define essential drugs for children by volume and by number of children that need a certain medicine is incomplete, as indications and severity of the conditions for which the drug is prescribed also play an important role [10]. Secondly, the method employed in our literature search may have introduced some bias toward outpatient drug consumption, thus underestimating the use of, for example, anesthetic or cardiovascular drugs. Clearly, hypertension or lipid disorders occur in children, and knowledge about these drugs in this population is important. However, these conditions are certainly not major causes of morbidity, and subsequent drug use in children and the research priorities lie elsewehere.

Furthermore, there are specific issues in pediatric clinical pharmacology that have remained unaddressed by the current product-related approach. First, the age distribution of the children participating in the trials does not reflect the actual medical needs. Drug use in children follows a pattern, with a relatively high percentage of children using a prescription drug in the first year of life [24] while the proportion of off-label and unlicensed drug use is highest (∼90%) in the vulnerable group of neonatal ICU patients [5]. These data are not reflected in the participation in the trials to obtain pediatric exclusivity, with neonates and infants being included in, respectively, 14 and 39% of the study groups. In fact, it is surprising to see that the majority of applications included children of a wide age range, thereby ignoring the delineation of age groups as defined in the ICH guidelines. This is problematic, as in the pediatric population significant age-related differences may exist in the pharmacokinetics and the effects of drugs [11]. Secondly, the effects of drugs (that are intended for chronic use) on development and maturation of children are largely unknown, but this issue has hardly been addressed. Third, off-label drugs are hardly or not studied. Only ten drugs in this category are under consideration for study by pharmaceutical companies (FDA website). From these ten drugs, six already have been refused by industry for studying, and have been referred to the National Institutes of Health to obtain the necessary information for rational use in pediatric populations. These clinical trials are at the moment awaiting funding [13, 18]. Surprisingly, in the same Tufts study that reports on a profit of $35 million US per drug granted exclusivity, it is also suggested that the current incentives for studying non-patent protected drugs are too low [29].

Finally, methodological research has remained underfunded by this approach. Any expansion of research will require specialized techniques that allow samples and data to be obtained in children with minimal discomfort and risk. For instance, most pharmacokinetic assays require an amount of blood that is too large for the average neonate, so highly sensitive assays need to be developed. Accurate assessment of drug effects on neuro-development and behavior also require further development, independently of studies with particular compounds.

The recently approved EU guidelines contain differences from the USA that may remedy some of the deficiencies indicated. It contains a section for the stimulation of off-patent drugs that can be granted a special label (PUMA), and data protection if data necessary to establish safety, quality and efficacy in children are submitted. The ‘Medicines Investigation for the Children of Europe’ program, funded by the EU, will be created to stimulate research of off-patent drugs. The proposed establishment of a Pediatric Committee, operating within the European Medicines Agency, will guard study of significant drugs for children and avoid unnecessary studies, provide free advice to industry, and stimulate long-term pharmacovigilance. It will also play a role in the implementation of the requirement for industry to submit data they already hold on use of their medicines in children. New drugs will not be granted Marketing Authorisation unless the need for pediatric research has been waived by the Pediatric Committee, or deferral of initiation or completion of an already approved Pediatric Investigation Plan has been agreed to by this committee. In addition, an EU network of investigators and trial centers will be formed [1]. Although elements of this network are now beginning to form, their funding is unclear and certainly not at the level provided to the patent holders by a patent extension. Also, it is not immediately clear why the EU measures will deliver, when this was not achieved with the formation of Pediatric Pharmacology Research Units and the oversight of research priorities by the FDA in the USA.

In conclusion, the schemes implemented in the US generated new knowledge and led to the rapid development of an infrastructure to carry out pediatric drug trials. Although these are certainly positive developments, we do believe that the findings of this survey warrant additional efforts to stimulate research on drugs used more frequently by children, and generally applicable methodological research, as at least the short-term effect of these initiatives seems to have drawn the focus of industry-sponsored research to the most profitable part of the market. The funding of the research we propose should not be problematic. The pediatric exclusivity schemes generate a flow of public money to the sponsoring drug companies because generic replacement and price reductions are postponed. There is no particular reason why these public funds could not be at least partly applied in an alternative manner.