Pediatric pharmacology: why do we need it ? Milica Bajcetic, MD,PhD ESDP Departrment for Clinical Research University Children’s Hospital & Department for Pharmacology, Clinical Pharmacology and Toxicology School of Medicine, University of Belgrade

Timeline 1930s beginning of development of Clinical Pharmacology (CP) Harry Gold (1899-1972) Cornell University, USA 1930s beginning of development of Clinical Pharmacology (CP) 1952, Harry Gold established CP 1960, Journal of Clinical Pharmacology & Therapeutics 1970, CP unit established in Nordic countries, UK and USA “…a special kind of investigator is required, one whose training has equipped him not only with the principles and techniques of laboratory pharmacology but also with knowledge of clinical medicine…”

CP postgraduate programme in Serbia 1975, School of Medicine, University of Novi Sad 1981, School of Medicine, University of Belgrade Until today more than 90 CP specialists and subspecialists fully trained

CP UNIT IN SERBIA 1989, Institute for Oncology and Radiology of Serbia, Belgrade 2005, Military Medical Academy 2003, Clinical Center of Serbia, Belgrade 1995, Clinical Center, Kragujevac 2008, University Children’s Hospital, Belgrade 2004, Center for Pharmacotherapy, Clinical Center, Niš

1930 - diethylene glycol poisoning - deaths 1948 - chloramphenicol - gray baby syndrome 1960 - thalidomide – phocomelia, etc.

Licensing system – ensures that medicines are examined for: Safety Quality Efficacy

RANDOMIZED,CONTROLLED CLINICAL TRIAL pharmacokinetics pharmacodynamics pharmacogenetics PHARMACOVIGILANCE PHARMACOEPIDEMIOLOGY PHARMACOECONOMY

RANDOMIZED,CONTROLLED CLINICAL TRIAL EXTRAPOLATION EXPERIENCE SENSATION pharmacokinetics pharmacodynamics pharmacogenetics PHARMACOVIGILANCE PHARMACOEPIDEMIOLOGY PHARMACOECONOMY

50-90% of medicines used have never actually been studied in children!

and psychological differences from adults. Children are vulnerable population with: developmental physiological and psychological differences from adults.

Absence of PK/PD/PG data →unreliable dose Safety and efficacy have not been assessed Lack of suitable pediatric formulations Absence of clinical trials in children leads to the use of off-label and unlicensed drugs

Fig. 2: Percentages of availabilty: Availability of oral formulation suitable for use in children in Serbia, Germany and USA Fig. 2.1. Percentage of active substances in a suitable oral dosage form Fig. 2.2. Percentage of active substances in a suitable oral dosage form and labelled for pediatrics < 12 years Fig. 2.3 Percentage of labelled active substances in the group of active substances in suitable oral dosage form

Off-label/Unlicensed Rates of Prescription % Ratio of Children Undergoing Off label/Unlicensed Drug Use %

Most Common Reason For Off Label Drug Use

OFF LABEL/UNLICENSED USE benefit harm no effect SUB DOSING OVER LACK OF PK/PD/PG DATA ADRs

Off-label/Unlicensed drug use and ADRs %

Doctors are men who prescribe medicines of which they know little, to cure diseases of which they know less, in human beings of whom they know nothing. Voltaire (1694-1778)

What is being done about this situation?

Closing the gap-USA legislation 2002 Best Pharmaceutical for Children Act 2003 Pediatric Research Equity Act 1998 Pediatric “Final Rule” 1997 Pediatric Exclusivity provision 1994 FDA Pediatric Rule 1992 Pediatric Pharmacology Research Network.Today 13 centers FDA Pediatric exlusivity labeling changes Up to 2008 -136 New doses,new precautions Drug studies included multiple therapeutic areas Studies included efficacy/safety,PK,PD Adressing unmet therapeutic need in children with diverse condition

EUROPE: SIGNS OF PROGRESS 1997 EMEA Note for guidance on clinical investigation of medical products in the pediatric population 1998 European Network for Drug Investigation in Children (Finland, France, Germany, Israel, Italy, the Netherlands, Sweden, Switzerland, UK) 2001 International Conference on Harmonisation ICH 2002 European Forum for Good Clinical Practice CESP: Better Medicines for Children 2001 2004 EU Commission released the first proposal for a Regulation on Medicinal Products for Paediatric Use 2006 Regulation agreed on June 1, 2006. 2007 January, Clinical drug researches in pediatrics allowed

www.esdppp.org