A Study case about FP7 - TINN Treat Infections in NeoNates Warsaw – September 2008 ������������������ ������������� �������������������� 1
Regulation 1901/2006 of the European parliament and the Council of Medicinal Products for Paediatric Use • To increase availability of medicines authorized for children • To increase the information on the use of medicinal products in the paediatric population • Entry in force 26 January 2007 2
Awards and incentives take account of the status of the particular medicinal product concerned 1. Products under developpement and yet to be authorized 2. Authorized products covered by intellectual property rights 3. Authorized products covered no longer by intellectual property rights PUMA (Paediatric Use Marketing Authorization) 1. Aggred PIP 2. Data in the paediatric population from new studies, paediatric litterature, dossier … 3. Incentives ? Limited … 4. Financial support from Framework Program 7 - FP7 3
To answer a FP7 call • Motivation • Call within the FP7 program • Scientific project • European Participants - Experts in the different fields of the project • Management team • Fulfill the deadline • Expérience 4
Call FP7-Health-2007-4.2.1 Adapting off-patent medecines to the specific needs of paediatric populations • Support will be given to studies dedicated to provide evidence for specific paediatric use of off-patent medicinal product currently used off-label. Studies include the assessement of pharmacokinetics (as well as data analysis and extrapolation by means of in silico models), efficacy and safety, and/or developpement of appropriate formulations. • Projects proposal must take into account the priority list of Off-patent Medicinal products of the Paediatric Working party of the European Medical Agency (EMEA), and of the regulation of the European parlement and of the Council on medicinal products for Paediatric use and amending Regulation (EED) n° 1768/92, Directive 2001/83/EC and Regulation (EC) n° 726/1004, Brussels, 29.9.2007 COM (2004) 599 final, 2004/0217 (COD). • Funding scheme : Collaborative Projects (Small or medium scale focused research projects with a maximum of E6,000,000 /project 5
Call FP7-Health-2007-4.2.1 Adapting off-patent medecines to the specific needs of paediatric populations 1. priority list EMEA 2. evidence for specific paediatric use 3. off-patent / off-label 4. appropriate formulations 5. pharmacokinetics 6. efficacy and safety 7. in silico models 8. Collaborative research Project / partenaires 9. E6,000,000 /project 6
Priority list Priority list of off-patent drugs with an objective of Public health In a first step , priority points were assigned to conditions, based on � the severity of the disease, � the paediatric age groups affected (with special priority to the neonatal population), � the non-availability of treatment alternatives � the high prevalence of the disease in the paediatric population In a second step , for each condition, published therapeutic rewievs were analysed to identify off-label products of therapeutic interest. 7
Priority List (June 2007) • Pain • Gastro-oesophagal reflux • INFECTION Ciprofloxacine Antifungal drugs : amphoB, fluconazole Antiviral drugs: foscarnet Antiretroviral drugs 8
Infection in neonates • Priority-list • High risk population • Health care problems (at birth with prematurity, hospitalisations..an long term with sequelae, drug toxicities…) - Mortality • Data are lacking on pharmacology (PK, dosage schedules..), efficacy and toxicity.. • Medical expérience, prescriptions… 9
• Ciprofloxacin is administered to treat neonates with sepsis caused by multiple resistant organisms, against which only ciprofloxacin is effective. • Fluconazole is administered to prevent and/or treat neonates with invasive candidiasis 10
Call FP7-Health-2007-4.2.1 Adapting off-patent medecines to the specific needs of paediatric populations • Yes 1. priority list EMEA • Yes : neonates 2. evidence for specific paediatric use • Yes in the neonatal 3. off-patent / off-label population 4. appropriate formulations • Yes/No (oral indication ?) 5. pharmacokinetics • Yes 6. efficacy and safety 7. in silico models • Yes • Yes 8. Collaborative Research Project / • Yes partenaires • !! 9. E6,000,000 /project 11
Initial proposal to neonatologists French Society of Neonatology Pharmacokinetics Pharm-dynamics Formulation Pharm-genetics Ciprofloxacin is administered Infectiology Methodo to treat neonates with sepsis caused by multiple resistant -logy organisms, against which only Clinical Trial European ciprofloxacin is effective. Design DataBase Ciprofloxacine Antifungals Fluconazole is administered to prevent and/or treat Foscarnet neonates with invasive candidiasis Neonatology centres Pharmacology centres Data Analysis Report Ciprofloxacine Antifungals Foscarnet 12
Why a FP7 project ? There are major practical and ethical issues in relation to studying medicines in the vulnerable group of preterm and term neonates such as: • limited number of neonates with comparable diseases. They represent only a small part of the population as compared to older children and adults, and the variation of specific types of diseases in this young subpopulation is higher than in the paediatric counterpart. In addition, diseases may affect only a small subcategory of patients. This is particularly true for neonates, representing only a small proportion of the paediatric population in Europe • major differences in drug disposition in the different age groups • need for adapted formulations • need for suitable methodological approaches for clinical trials • limited number of trained investigators with expertise in neonatal clinical trials and inadequate critical mass of investigators in any single European country • lack of an adequate drug monitoring program in this population • major ethical issues 13
Concept and Objectives The TINN project aims at conducting two clinical trials in the groups of preterm and term neonates � Evaluation of the pharmacokinetcis, efficacy and safety of ciprofloxacin in pre term and term neonates � Evaluation of the pharmacokinetcis, efficacy and safety of ciprofloxacin in preterm and term neonates The final objective is to validate PIPs for the two drugs and apply for a PUMA 14
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Identify partners… • Scientists Discussions with experts, national contacts, specialists (neonatalogy, methodology, Ethics, PK modelisation…) Medline (fluconazole – Italy…) Rapid positive answer • Management team 16
Partenaires • France CIC network, French Society of Neonatalogy, • Belgium Neonat • Nederlans Neonat • Danemark Néonat • UK Pharmacovigilance / Ethics • Italy Epidémiology / Neonat • Germany Pharmacogebetics • Sweden Pharmacology, Neonat • SME : EPMC Pharma, ClinInfo • Inserm Transfer • Teddy, Paedifon 17
The partners of the TINN project agreed to work simultaneously on the two drugs in a unique collaborative project as: the two medicines have common features . They • are used off-patent in all European countries • are administered to cure rare infectious diseases • are prescribed in identical groups of preterm and term neonates with high risk infection • are administered from dosage forms designed for adults or older children • are therefore used in a unique clinical setting of neonatal intensive care the two medicines are not properly evaluated in neonates . They • require data on pharmacokinetics, efficacy and safety • and therefore, require specialists in paediatric methodology, pharmaceutics, pharmacokinetics, neonatologists trained in clinical evaluations • require high level of expertise in Ethics 18
Write the project • S1: Scientific and/or technical quality, relevant to the topics addressed by the call • S2: Implementation : Worckpackages • S3: Impact - Deliverables • S4: Ethical Issues • S5: Consideration of gender aspects 19
Workpackages • WP1: Co-ordination and Management of the Consortium • WP2 : Preclinical studies • WP3 : Ciprofloxacin trial • WP4 : Fluconazole trial • WP5 : Ethics and Safety • WP6 : Organisation and monitoring of the trials • WP7 : Diffusion of information 20
WP2 Preclinical studies • Juvenile animal studies • In silico experiments 21
Non clinical Testing in Juvenile Animals PIP, PUMA In vitro test Preclinical studies Clinical trial & in silico EMEA guidelines * * Guideline on the need for non-clinical testing in juvenile animals on human pharmaceuticals for paeditric indications, EMEA Committee for human medicinal products (CHMP), 2005 22
Phenopups - a plate-forme to phenotype newborn mice Physiological tests � Breathing � ECG HR variabilty � Thermoregulation � Ultrasonic vocalizations � Motor activity Psychomotor development � Reflexes � Memory and learning Other systems � Sensitivity to hypoxia � Blood samples 23
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