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
European Congenital Heart Disease Organisation (ECHDO)
Berlin 23 24 March 2007

The labelled percentage of 41 standard drugs used in a neonatal

and pediatric intensive care unit
(Heidelberg, 1981).

100%

newborns

infants

13

children
23

50%
57%
32%

0%

11%
H.W. Seyberth, Kinderarzt 1984

Consequences of unlicenced and off label drug

prescriptions:
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

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?

Adverse Drug Reactions (ADR) of

unlicensed and of label drug prescription in paediatrics
ADR
%
10 -

In label and licensed

Of label and unlicensed
6.0

5 -

3.9

3.4
1.4

On the wards (UK)

(Turner et al, Acta Paed. 1999)

In the outpatient clinics (FR)

(Horen et al, Brit J Clin Pharm 2002)

What has happened in the past ?

Some examples !

Adverse effects of geriatric heart failure therapy

applied to the preterm infant with sPDA:
fluid restriction

furosemide

marked volume depletion

renal hypoperfusion
PG-stimulation
nephrocalcinosis
arrhythmias with
cerebral bleeding

digoxin

intestinal perforation
renal failure

Congenital salt losing tubulopathies (SLTs)

Different age at manifestation and ontogeny of targets
(Jeck et al., AJ P 2005)

Furosemid-SLT : NKCC2
Polyhydramnios
Age at first

12/12
antenatal: 12/12

Affected nephron
segment

0/13
<1 year: 1/13
1-5 years: 4/13

6-13 years: 8/13

presentation
Postnatal
leading
symptoms

Thiazid-SLT : NCCT

polyuria
hyponatremia
hypotension (shock)
hypercalciuria
nephrocalcinosis

thick ascending limb

hypokalemia
carpopedal spasms
hypomagnesemia
hypocalciuria
growth retardation

distal convolute

Morphine plasma concentration [g/l]

at time point of pain recovery

Medium analgesic dosage of morphine

in children with an age between 0 and 6 years
p < 0.01
40

dosis:
0.05 mg/kg/min infusion
rate until painlessness

30

20

10

0 - year
n=5

2 - 4 year
n=5

6 year
n=4
(Olkkola et al., CPT 1988)

Legislative Incentives
in Europe?

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

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

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 Pediatric Use Marketing Authorisation (P.U.M.A.) :

enabeling 10-years data protection

use of existing brand name (brand recognition)

amended data requirements

Institutional or horizontal key measures of the EU-Regulation:

A new expert paediatric committe (PC) at the EMEA, which negotiates w

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

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

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:

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

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 )
Conditions

Products

Needs

Age Group

Sedation

Chloralhydrate
Propofol
AC-inhibitors
Diuretics
Catecholamines
Morphine
NSAIDs
Steroids (inhaled,
oral)

Efficacy, safety
for procedures

All age groups

Heart failure

Pain
Obstr.lung dis.

Efficacy, safety

All age groups incl.

neonates

Efficacy, safety
Longterm safety
Longterm safety,
efficacy, safety

< 6 months All

age groups
All age groups
< 1 year

Child Health in FPVII (2007-2013)

2nd 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 !)

Members of the European Network Drug Investigation in Children

(ENDIC1997 in the ESDP)

Elisabeth Autret-Leca, Tours

Jean-Paul Langhendries, Liege

Maurizio Bonati, Milano

Grard Pons, Paris

Imti Choonara, Derby

Anders Rane, Stockholm

Rafal Gorodischer, Beer-Sheva

Hannsjrg W. Seyberth, Marburg

Kalle Hoppu, Helsiniki

John N. van den Anker, Rotterdam

Evelyne Jacqz-Aigrain, Paris

Bart van Overmeire, Antwerp

Thank you for your attention !

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
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 )

Anaesthesiology
Antiinfectious therapy
Cardiology
Chemotherapy
Diabetes
Epilepsy
Immunology

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