1. European Congenital Heart Disease Organisation (ECHDO) Berlin 23 – 24 March 2007 H. W. Seyberth Chairman of the Commission on Drug Safety of German Society of Pediatrics (DGKJ) Member of the Paediatric Working Party (PEG) at the EMEA Save Drugs for Children with CHD: New European Regulation

2. The labelled percentage of 41 “standard drugs” used in a neonatal and pediatric intensive care unit (Heidelberg, 1981). – – newborns infantschildren 100% 50% 0% 513 23 32% 57% 11% H.W. Seyberth, Kinderarzt 1984

3. Consequences of unlicenced and off label drug perscriptions:  No adequate pediatric formulations  No dosing regimen  No warning of possible adverse drug reactions  No information about possible drug interactions  No product liability for the drug by the sponsor  No long term surveillance

4. When we choose a drug for a child... We rely on: - Personal experience (trial/error)? - Advice from colleagues/mentors? - Anecdotal reports in the literatur? - Extrapolation from adult data? - Small „trending“/inclusive trials?

5. - - 10 5 0 3.9 6.0 1.4 3.4 ADR % In label and licensed Of label and unlicensed On the wards (UK) In the outpatient clinics (FR) (Turner et al, Acta Paed. 1999) (Horen et al, Brit J Clin Pharm 2002) Adverse Drug Reactions (ADR) of unlicensed and of label drug prescription in paediatrics

6. What has happened in the past ? Some examples !

7. fluid restriction furosemide digoxin NSAID´s ACE- inhibitor Adverse effects of geriatric heart failure therapy applied to the preterm infant with sPDA: arrhythmias with cerebral bleeding marked volume depletion renal hypoperfusion PG-stimulation nephrocalcinosis intestinal perforation renal failure

8. Congenital salt losing tubulopathies (SLTs) Different age at manifestation and ontogeny of targets (Jeck et al., AJ P 2005) (Jeck et al., AJ P 2005) Thiazid - SLT : NCCT Furosemid -SLT : NKCC2 Polyhydramnios 12/12 0/13 Postnatal leading symptoms polyuria hyponatremia hypotension (shock) hypercalciuria nephrocalcinosis hypokalemia carpopedal spasms hypomagnesemia hypocalciuria growth retardation Age at first presentation antenatal: 12/12 <1 year: 1/13 1-5 years: 4/13 6-13 years: 8/13 thick ascending limbdistal convolute Affected nephron segment

9. Medium analgesic dosage of morphine in children with an age between 0 and 6 years (Olkkola et al., CPT 1988) 0 10 20 30 40 0 - ½ year n = 5 6 year n = 4 2 - 4 year n = 5 Morphine plasma concentration [µg/l] at time point of pain recovery p < 0.01 dosis: 0.05 mg/kg/min infusion rate until painlessness

10. Legislative Incentives in Europe?

11. Objectives of the EU-Regulation on Medicinal Products for Paediatric Use To improve the health of the children of Europe, by: - increasing high quality research into medicines for them - promoting the development and authorization of such medicines - improving the information on medicines designed for children While avoiding unnecessary studies in children and not delaying the authorization of medicines for adults

12. Key measures for patent medicines Requirement at the time of applications for new medicines for: Data in children as agreed by PC or A waiver from requirement or A deferral of the timing of the studies

13. Key measures for patented medicines Key measures for patented medicines Rewards for studies conduced in children: - 6-months extension of the supplementory protection certificate (in-effect, a patent extension) - For orphan medicines, 2-years additional market exclusivity (10+2 years)

14. Key measures for off-patent medicines The Pediatric Use Marketing Authorisation (P.U.M.A.) : - enabeling 10-years data protection - use of existing brand name (brand recognition) - amended data requirements

15. Institutional or horizontal key measures of the EU-Regulation: A new expert paediatric committe (PC) at the EMEA, which negotiates with the MAH the padiatric investigation plan (PIP) Free scientific advice from EMEA European network of experts Information tools – inventory of therapeutic needs, new product labelling requirements, database of studies Public funding for studies into off-patent medicines, e.g. accepted application in the FP7 Enhanced safety monitoring for marked products

16. Specific paediatric needs and priorities in Europe (particular for the neonates) : Analgesics Sedatives Immunomodulators, e.g. rheuma and TPL Antiepileptic agents Anticongestive and antiarrhythmic agents Antihypertensive agents Antiobstructive agents Cytostatic agents Not included: Paed. anaesthesiology and child psychiatry

17. EMEA Priority-List of Off-Patent Medicinal Products for Paediatric Studies in the FP7 ( http://www.emea.eu.int/pdfs/human/peg/49677706en.pdf ) Methodology of Selection: http://www.emea.eu.int/pdfs/human/peg/49677706en.pdf Severtity of the disease Paediatric age groups affected (with special regard to the neonatal population) Non-availability of treatment alternatives High prevalence of the disease in the paediatric population High level of evidence available and known or suspected efficacy or safety issues

18. Some Examples from the EMEA Priority-List of Off-Patent Medicinal Products for Paediatric Studies ( http://www.emea.eu.int/pdfs/human/peg/49677706en.pdf ) http://www.emea.eu.int/pdfs/human/peg/49677706en.pdf ConditionsProductsNeedsAge Group Sedation Heart failure Pain Obstr.lung dis. Chloralhydrate Propofol AC-inhibitors Diuretics Catecholamines Morphine NSAID´s Steroids (inhaled, oral) Efficacy, safety for procedures Efficacy, safety Efficacy, safety Longterm safety Longterm safety, efficacy, safety All age groups All age groups incl. neonates < 6 months All age groups All age groups < 1 year

19. Child Health in FPVII (2007-2013) 2 nd call due June 07 and 3rd call due September 07 Overarching topics on Child Health: Adopting off-patent medicines to specific needs of paediatric populations Studies include the assessment of PK-data, efficacy, safety and/or the development of age appropriate formulation Funding scheme: collaborative project with a maximum of EC contribution of 3 000 000 € for each (3 year) project ( 30 Mio € are available !)

20. Members of the European Network Drug Investigation in Children (ENDIC1997 in the ESDP) Elisabeth Autret-Leca, ToursJean-Paul Langhendries, Liege Maurizio Bonati, MilanoGérard Pons, Paris Imti Choonara, DerbyAnders Rane, Stockholm Rafaël Gorodischer, Beer-ShevaHannsjörg W. Seyberth, Marburg Kalle Hoppu, HelsinikiJohn N. van den Anker, Rotterdam Evelyne Jacqz-Aigrain, Paris Bart van Overmeire, Antwerp

21. Thank you for your attention !

22. EMEA=European Medicines Agency Milestones of the EU Paediatric regulation EC Round Table, EMEA - 18 December 1997 EU Council resolution - 14 December 2000 Public consultations - 2002 and 2004 EU Commission proposal - 29 September 2004 European Parliament 1. vote - 7. Sept. 2005 Adoption by EU Council - 9 December 2005 2nd vote and adoption by EP - 1. June 2006 Entry into force - 26. January 2007

23. Assessment of Paediatric Needs by the Paediatric Expert Group at the EMEA in the last three years ( http://www.emea.eu.int/htms/human/peg/pegassessment.htm )http://www.emea.eu.int/htms/human/peg/pegassessment.htm Anaesthesiology Antiinfectious therapy Cardiology Chemotherapy Diabetes Epilepsy Immunology Migraine Obstructive Lung disease Pain Rheumatology (Gastroenterology) (Child-Psychiatry)