Introduction 15 4 2 25 In 1997, the Food and Drug Administration (FDA) and the Congress introduced the Food and Drug Administration Modernization Act (FDAMA), and this was followed by the Best Pharmaceuticals for Children Act. Closely linked to this legislation is the Pediatric Rule (1998), which requires the industry to perform research in the pediatric population. In the European Union (EU), final legislation on this topic has been approved and will come into effect at the beginning of 2007. In both continents, the measures taken to address the problems broadly follow the same pattern. The first incentive is aimed at new medicines and intended for products covered by a patent or a supplementary protection certificate (SPC). For these drugs, a 6-month extension of market exclusivity is granted if a pediatric study is performed. The second incentive has the objective of increasing the knowledge on drugs that are no longer patent protected. In order to obtain the data necessary to establish safety, quality and efficacy specifically in children, either funding for the studies (USA) or market exclusivity (a so-called Pediatric Use Marketing Authorization—PUMA) can be given. Central to the second incentive is that experts are involved in determining for which drugs the greatest medical need exists and in ensuring that these drugs will be given priority. In the USA, the FDA plays this central role, and in the EU, a Pediatric Committee will be established within the European Medicines Agency (EMEA) which will be given a similar role. 1 At the brink of implementing new programs (EU) or decisions on continuation of existing programs (USA), we questioned what the influence of the pediatric exclusivity regulation has been on pediatric drug development. We evaluated the drugs that are granted pediatric exclusivity in the USA by studying research that has been performed as a consequence of the exclusivity provision, and by comparing the drugs granted pediatric exclusivity with medicines actually used by children. Materials and methods 17 6 17 26 7 8 Literature search and selection strategy Child, preschool (or) child (or) infant (or) infant, newborn (or) adolescent (or) pediatric (or) paediatric (or) paediatrics. Pharmaceutical preparations (or) drugs, non-prescription (or) drugs, generic (or) drug, therapy (or) prescriptions, drug (or) medicine (or) medication. Drug utilization (or) pharmacoepidemiology (or) drug utilization review. Step 2: the references contained in articles identified in step 1 were examined to identify further relevant studies. Step 3: based on the titles and abstracts of the papers, we next identified and then located full-text copies of 35 potentially relevant studies for closer examination. Study performed in the industrialized world, defined as in Europe, North America, Australia and New Zealand. Study population of children from 0 to at least 14 years, to include all age groups (neonates, infants, children and adolescents). Sufficient information in the paper about drug utilization to classify 90% of the drugs in an ATC drug groups. Avoidance of selection bias by exclusion of voluntary surveys.  Step 5: inclusion of nine papers meeting all selection criteria. Results Pediatric exclusivity provision 1 Table 1 Active moieties granted pediatric exclusivity according to ATC group Drug category Number of drugs (% of total) Most frequent drug classes Number of drugs Central nervous system 24 (19%) Anti-depressants 8 Psychostimulants, agents used for ADHD and nootropics 4 Anti-epileptics 3 General anaesthetics 3 Anti-migraine preparations 2 Cardiovascular system 21 (16%) ACE inhibitors, plain 6 HMG-CoA reductase inhibitors 5 Beta-blocking agents 4 Alimentary tract and metabolism 16 (12%) Drugs for peptic ulcer and gastro-oesophageal reflux disease 5 Oral blood glucose lowering drugs 4 Anti-infectives for systemic use 15 (12%) Direct acting antivirals 10 Antibacterials for systemic use 4 Antineoplastic and immunomodulating agents 14 (11%) Other antineoplastic agents 5 Antimetabolites 3 Alkylating agents 2 Musculo-skeletal system 7 (5%) Anti-inflammatory and anti-rheumatic products, non-steroids 6 Drugs affecting bone structure and mineralization 1 Respiratory system 10 (8%) Antihistamines for systemic use 4 Drugs for obstructive airway disease 3 Decongestants and other nasal preparations for topical use 2 Sensory organs 10 (8%) Antiglaucoma preparations and miotics 4 Decongestants and anti-allergics 3 Dermatologicals 6 (5%) Corticosteroids, potent (group 3) 3 Genito-urinary system and sex-hormones 3 (3%) Other urologicals, including antispasmodics 2 Blood and blood forming organs 2 (2%) Anti-thrombotic agents 1 Systemic hormonal preparations 1 (1%) Hypothalamic hormones 1 Parasitology 1 (1%) Anti-malarials 1 Total 130 (100%)   n n For 42% of the drugs granted pediatric exclusivity and for which information was available (50 out of 118), the information obtained from the pediatric studies led to an approved pediatric indication. 1 Drug utilization by children and adults 2 3 Table 2 Characteristics of included studies on pediatric drug utilization Author (year) Setting Population size Age range (y) Number of prescriptions 14 Pharmacy dispensing records in-and outpatients 1,704 0–14 5,876 21 Prescriptions of general practitioners a 0–19 8,215 28 Pharmacoepidemiological prescription database outpatients 48,091 0–15 154,189 b 24 Pharmacy dispensing records outpatients 15,001 0–16 373,925 12 Prescriptions pediatric outpatients 12,628 0–16 33,140 16 Prescriptions general pediatric hospitals 1,325 0–14 4,265 23 Pharmacy dispensing records outpatients 18,943 0–16 66,222 30 Pharmacy dispensing records outpatients 357,784 0–16 644,817 22 Prescriptions outpatients by GPs and pediatricians 12,264 0–14 27,486 a b Table 3 Drug utilization pattern in children Drug category % of prescriptions Frequent used drug classes Respiratory system 30 % Drugs for obstructive airway disease Nasal preparations Cough and cold preparations Antihistamines for systemic use General anti-infectives, systemic 28% Antibacterials for systemic use Dermatologicals 12% Antifungals for dermatological use Emollients and protectives Corticosteroids, dermatological preparations Sensory organs 7% Ophtalmologicals Otologicals Central nervous system 4% Analgesics/ antipyretics Psychostimulants, agents used for ADHD and nootropics Anti-epileptics Hormones 3% Corticosteroids, for systemic use Blood and blood forming organs 3% Vitamin K Alimentary tract and metabolism 2% Drugs for peptic ulcer and gastro-oesophageal reflux disease Insulins and analogues Musculo-skeletal system 2% Anti-inflammatory and anti-rheumatic products, non-steroids Genito-urinary system and sex-hormones 2% Hormonal contraceptives for systemic use Cardiovascular system 1% Diuretics Other <1%  Total 105% (exceeds 100% due to rounding) 4 Table 4 Drug utilization patterns in adults, according to the drug sales in North America over the period May 2004–May 2005 Drug category Adult prescriptions Central nervous system 23% Cardiovascular system 19% Alimentary tract and metabolism 14% Respiratory system 9% General anti-infectives, systemic 8% Musculo-skeletal system 6% Genito-urinary system and sex-hormones 6% Other 2% Antineoplastic and immunomodulating agents 4% Dermatologicals 3% Blood and blood forming organs 3% Sensory organs 2% Total 100% Discussion 20 1 3 19 27 9 1 29 10 24 5 11 13 18 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. 1 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.