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:Save Drugs for Children with CHD:

New European RegulationNew European Regulation

The labelled percentage of 41 “standard drugs” used in a neonatal and pediatric intensive care unit

(Heidelberg, 1981).

– newborns infants children100%

50%

0%

5 13 23

32%

57%

11%

H.W. Seyberth, Kinderarzt 1984

Consequences of unlicenced and off label drug Consequences of unlicenced and off label drug perscriptions: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 ...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)

AdverseAdverse Drug Reactions (ADR) of Drug Reactions (ADR) of

unlicensed and of label drug prescription in paediatricsunlicensed 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 Adverse effects of geriatric heart failure therapy applied to the preterm infant with sPDA:applied to the preterm infant with sPDA:

arrhythmias with cerebral bleeding

marked volume depletion renal hypoperfusion

PG-stimulationnephrocalcinosis

intestinal perforationrenal failure

Congenital salt losing tubulopathies (SLTs)Congenital salt losing tubulopathies (SLTs)Different aDifferent age at manifestation and ontogeny of targets ge at manifestation and ontogeny of targets (Jeck et al., AJ P 2005)(Jeck et al., AJ P 2005)

Thiazid-SLT : NCCTFurosemid-SLT : NKCC2

Polyhydramnios 12/12 0/13

Postnatal leading symptoms

polyuria hyponatremiahypotension (shock) hypercalciurianephrocalcinosis

hypokalemiacarpopedal spasms hypomagnesemiahypocalciuriagrowth retardation

Age at first

presentationantenatal: 12/12

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

6-13 years: 8/13

thick ascending limb distal convoluteAffected 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 = 5M

orp

hin

e p

lasm

a c

on

cen

trat

ion

[µg

/l]a

t tim

e p

oin

t of p

ain

re

cove

ry

p < 0.01

dosis:0.05 mg/kg/min infusionrate until painlessness

Legislative Incentives in Europe?

Legislative Incentives in Europe?

Objectives of the EU-Regulation on Medicinal Products Objectives of the EU-Regulation on Medicinal Products for Paediatric Use 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 medicinesKey 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 Key measures for patentedpatented medicines 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 Key measures for offoff-patent medicines-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 horizontalInstitutional or horizontal key measures of the EU-Regulation: 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

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 GroupSedation

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

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 specificneeds of paediatric populations

Studies include the assessment of PK-data, efficacy,safety and/or the development of age appropriateformulation

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 !

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

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)