European Congenital Heart Disease Organisation (ECHDO) Berlin 23

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
infants
children
100
23
5
13

50
57
32
11
0
H.W. Seyberth, Kinderarzt 1984
3
Consequences of unlicenced and off label drug
perscriptions
? 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
? No adequate pediatric formulations
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
Adverse Drug Reactions (ADR) of unlicensed and
of label drug prescription in paediatrics
ADR
In label and licensed
-
10
Of label and unlicensed
6.0
-
5
3.9
3.4
1.4
0
On the wards (UK)
In the outpatient clinics (FR)
(Horen et al, Brit J Clin Pharm 2002)
(Turner et al, Acta Paed. 1999)
6
What has happened in the past ?Some examples !
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Adverse effects of geriatric heart failure
therapy applied to the preterm infant with sPDA
fluid restriction
furosemide

digoxin
NSAIDs ACE- inhibitor
8
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

lt1 year 1/13 1-5 years 4/13 6-13
years 8/13
Age at first presentation
antenatal 12/12


polyuria hyponatremia hypotension (shock)
hypercalciuria nephrocalcinosis
hypokalemia carpopedal spasms hypomagnesemia hypo
calciuria growth retardation
Postnatal leading symptoms
9
Medium analgesic dosage of morphine in children
with an age between 0 and 6 years
p lt 0.01
40
dosis 0.05 mg/kg/min infusion rate until
painlessness
30
20
Morphine plasma concentration µg/l at time
point of pain recovery
10
0
0 - ½ year n 5
6 year n 4
2 - 4 year n 5
(Olkkola et al., CPT 1988)
10
Legislative Incentives in Europe?
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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

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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
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 (102 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.p
df ) Methodology of Selection

• 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/4
9677706en.pdf )
Conditions Products Needs Age Group
Sedation Heart failure Pain Obstr.lung dis. Chloralhydrate Propofol AC-inhibitors Diuretics Catecholamines Morphine NSAIDs 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 lt 6 months All age groups All age groups lt 1 year
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Child Health in FPVII (2007-2013) 2nd call due
June 07 and 3rd call due September 07Overarching
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 !)

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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

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Thank you for your attention !
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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

EMEAEuropean Medicines Agency
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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/pega
ssessment.htm )

• Migraine
• Obstructive Lung disease
• Pain
• Rheumatology
• (Gastroenterology)
• (Child-Psychiatry)

• Anaesthesiology
• Antiinfectious therapy
• Cardiology
• Chemotherapy
• Diabetes
• Epilepsy
• Immunology