Specific topics are proposed will address the following research issues related to child health and paediatric diseases: Paediatric formulations of drugs against HIV/AIDS, malaria and tuberculosis, Combined forms of diabetes in children, Promoting healthy behaviour in children and adolescents, Addressing knowledge gaps in pregnancy malaria, Innovative approaches for the development of neonatal vaccines International Co-operation : Health care intervention research – improving pre-natal and maternal care. Implications for child health and paediatric diseases should be taken into account whenever appropriate in all research projects in this Theme. In addition, support will be given in particular to specific clinical studies to provide evidence for the appropriate use of off-patent products currently used off-label in paediatric populations.
Pediatric Clinical Pharmacology
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
The labelled percentage of 41 “standard drugs” used in a neonatal and pediatric intensive care unit (Heidelberg, 1981). – – newborns infants children 100% 50% 0% 5 13 23 32% 57% 11% H.W. Seyberth, Kinderarzt 1984
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
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?
- - 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
What has happened in the past ? Some examples !
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
Congenital salt losing tubulopathies (SLTs) Different age at manifestation and ontogeny of targets (Jeck et al., AJ P 2005) Thiazid - SLT : NCCT Furosemid -SLT : NKCC2 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 Polyhydramnios 12/12 0/13 thick ascending limb distal convolute Affected nephron segment
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
Objectives of the EU-Regulation on Medicinal Products for Paediatric Use <ul><li>To improve the health of the children of Europe, by: </li></ul><ul><li>- increasing high quality research into medicines for them </li></ul><ul><li>- promoting the development and authorization of such medicines </li></ul><ul><li>- improving the information on medicines designed for children </li></ul><ul><li>While avoiding unnecessary studies in children and not delaying the authorization of medicines for adults </li></ul>
Key measures for patent medicines Requirement at the time of applications for new medicines for: <ul><li>Data in children as agreed by PC or </li></ul><ul><li>A waiver from requirement or </li></ul><ul><li>A deferral of the timing of the studies </li></ul>
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)
Key measures for off -patent medicines The P ediatric U se M arketing A uthorisation (P.U.M.A.) : <ul><li>enabeling 10-years data protection </li></ul><ul><li>- use of existing brand name (brand recognition) </li></ul><ul><li>- amended data requirements </li></ul>
Institutional or horizontal key measures of the EU-Regulation: <ul><li>A new expert paediatric committe (PC) at the EMEA, which negotiates with the MAH the padiatric investigation plan (PIP) </li></ul><ul><li>Free scientific advice from EMEA </li></ul><ul><li>European network of experts </li></ul><ul><li>Information tools – inventory of therapeutic needs, new product labelling requirements, database of studies </li></ul><ul><li>Public funding for studies into off-patent medicines, e.g. accepted </li></ul><ul><li>application in the FP7 </li></ul><ul><li>Enhanced safety monitoring for marked products </li></ul>
Specific paediatric needs and priorities in Europe (particular for the neonates) : <ul><li>Analgesics </li></ul><ul><li>Sedatives </li></ul><ul><li>Immunomodulators, e.g. rheuma and TPL </li></ul><ul><li>Antiepileptic agents </li></ul><ul><li>Anticongestive and antiarrhythmic agents </li></ul><ul><li>Antihypertensive agents </li></ul><ul><li>Antiobstructive agents </li></ul><ul><li>Cytostatic agents </li></ul><ul><li>Not included: Paed. anaesthesiology and child psychiatry </li></ul>
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: <ul><li>Severtity of the disease </li></ul><ul><li>Paediatric age groups affected (with special regard to the neonatal population) </li></ul><ul><li>Non-availability of treatment alternatives </li></ul><ul><li>High prevalence of the disease in the paediatric population </li></ul><ul><li>High level of evidence available and known or suspected efficacy or safety issues </li></ul>
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 ) All age groups All age groups incl. neonates < 6 months All age groups All age groups < 1 year Efficacy, safety for procedures Efficacy, safety Efficacy, safety Longterm safety Longterm safety, efficacy, safety Chloralhydrate Propofol AC-inhibitors Diuretics Catecholamines Morphine NSAID´s Steroids (inhaled, oral) Sedation Heart failure Pain Obstr.lung dis. Age Group Needs Products Conditions
Child Health in FPVII (2007-2013) 2 nd call due June 07 and 3rd call due September 07 Overarching topics on Child Health : <ul><li>Adopting off-patent medicines to specific </li></ul><ul><li>needs of paediatric populations </li></ul><ul><li>Studies include the assessment of PK-data, efficacy, </li></ul><ul><li>safety and/or the development of age appropriate </li></ul><ul><li>formulation </li></ul><ul><li>Funding scheme: collaborative project with a </li></ul><ul><li>maximum of EC contribution of 3 000 000 € </li></ul><ul><li>for each (3 year) project ( 30 Mio € are available ! ) </li></ul>
Members of the European Network Drug Investigation in Children (ENDIC1997 in the ESDP) Elisabeth Autret-Leca, Tours Jean-Paul Langhendries, Liege Maurizio Bonati, Milano Gérard Pons, Paris Imti Choonara, Derby Anders Rane, Stockholm Rafaël Gorodischer, Beer-Sheva Hannsjörg W. Seyberth, Marburg Kalle Hoppu, Helsiniki John N. van den Anker, Rotterdam Evelyne Jacqz-Aigrain, Paris Bart van Overmeire, Antwerp
Milestones of the EU Paediatric regulation <ul><li>EC Round Table, EMEA - 18 December 1997 </li></ul><ul><li>EU Council resolution - 14 December 2000 </li></ul><ul><li>Public consultations - 2002 and 2004 </li></ul><ul><li>EU Commission proposal - 29 September 2004 </li></ul><ul><li>European Parliament 1. vote - 7. Sept. 2005 </li></ul><ul><li>Adoption by EU Council - 9 December 2005 </li></ul><ul><li>2nd vote and adoption by EP - 1. June 2006 </li></ul><ul><li>Entry into force - 26. January 2007 </li></ul>EMEA=European Medicines Agency
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 ) <ul><li>Anaesthesiology </li></ul><ul><li>Antiinfectious therapy </li></ul><ul><li>Cardiology </li></ul><ul><li>Chemotherapy </li></ul><ul><li>Diabetes </li></ul><ul><li>Epilepsy </li></ul><ul><li>Immunology </li></ul><ul><li>Migraine </li></ul><ul><li>Obstructive Lung disease </li></ul><ul><li>Pain </li></ul><ul><li>Rheumatology </li></ul><ul><li>(Gastroenterology) </li></ul><ul><li>(Child-Psychiatry) </li></ul>
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