Transcript Pediatric Clinical Pharmacology

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
5
13
children
23
50%
57%
32%
0%
11%
H.W. Seyberth, Kinderarzt 1984
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
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
0
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
marked volume depletion
renal hypoperfusion
furosemide
PG-stimulation
nephrocalcinosis
digoxin
arrhythmias with
cerebral bleeding
NSAID´s
ACE- inhibitor
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
hypokalemia
hyponatremia
hypotension (shock)
hypercalciuria
nephrocalcinosis
carpopedal spasms
hypomagnesemia
hypocalciuria
growth retardation
thick ascending limb
distal convolute
Morphine plasma concentration [µg/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
30
dosis:
0.05 mg/kg/min infusion
rate until painlessness
20
10
0
0 - ½ 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):
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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
NSAID´s
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
< 6 months
Longterm safety All age groups
Longterm safety, All age groups
efficacy, safety
< 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
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
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 )
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Anaesthesiology
Antiinfectious therapy
Cardiology
Chemotherapy
Diabetes
Epilepsy
Immunology
• Migraine
• Obstructive Lung
disease
• Pain
• Rheumatology
• (Gastroenterology)
• (Child-Psychiatry)