A Study case about FP7 - TINN Treat Infections in NeoNates Warsaw - - PowerPoint PPT Presentation

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A Study case about FP7 - TINN Treat Infections in NeoNates Warsaw – September 2008

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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

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Awards and incentives take account of the status

• f 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

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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

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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

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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

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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.

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Priority List (June 2007)

• Pain
• Gastro-oesophagal reflux
• INFECTION

Ciprofloxacine Antifungal drugs : amphoB, fluconazole Antiviral drugs: foscarnet Antiretroviral drugs

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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…

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• 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

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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
• Yes
• Yes : neonates
• Yes in the neonatal

population

• Yes/No (oral indication ?)
• Yes
• Yes
• Yes
• Yes
• !!

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Antifungals Pharmacokinetics Pharm-dynamics Pharm-genetics Formulation Infectiology Clinical Trial Design European DataBase Ciprofloxacine Foscarnet

Methodo

• logy

Neonatology centres Pharmacology centres Data Analysis Report Ciprofloxacine Antifungals Foscarnet

Initial proposal to neonatologists French Society of Neonatology

Ciprofloxacin is administered to treat neonates with sepsis caused by multiple resistant

• rganisms, against which only

ciprofloxacin is effective. Fluconazole is administered to prevent and/or treat neonates with invasive candidiasis

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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

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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

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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

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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

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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

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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

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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

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WP2 Preclinical studies

• Juvenile animal studies
• In silico experiments

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Non clinical Testing in Juvenile Animals

In vitro test & in silico Preclinical studies Clinical trial EMEA guidelines * PIP, PUMA

* 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

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Physiological tests Breathing

ECG HR variabilty Thermoregulation Ultrasonic vocalizations Motor activity

Psychomotor development

Reflexes

Memory and learning

Other systems

Sensitivity to hypoxia Blood samples

Phenopups - a plate-forme to phenotype newborn mice

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Validity – Proof of concept

• FDA 2006

Guidance for industry. « Non-clinical safety evaluation of pediatric drug products »

rats / mice

• Developmental neurology
• Kidney system
• Pulmonary system
• Immunity
• Publications Inserm U676 : rats / souris
• Respitation
• Sleep
• Learning
• Anticipation
• Phenobarbital / newborn rats (Farwell 1990;

Fonseca 1976; Diaz 1977)

• Neurotoxicity of 'hexachlorophène

rats, monkeys (Towfighi 1980)

• Convulsions / théophylline

(Mares et al. 1994; Yokoyama et al. 1997)

• Neuroprotection / mélatonine

Ongoing animal trial (Bouslama et al. 2006)

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WP3 : ciprofloxacin trial

Objectives

• Define and validate the components of a PIP for

ciprofloxacin in neonates, including a trial designed to

• btain high quality data on the pharmacokinetics,

efficacy and tolerance of ciprofloxacin in preterm and term neonates

• Apply for European and/or national agreements

(including a PIP, ethical authorizations)

• Implement the PIP

Analyse the trial and report on the results

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Report about trial for PUMA application (with WP7) and submission to peer-reviewed journal

3.16

Definitive analysis of the ciprofloxacin pivotal trial

3.15

First patient recruited in the reconfigured registry

3.14

Database lock of Ciprofloxacin pivotal trial

3.13

Close recruitment of ciprofloxacin pivotal trial

3.12

Interim analysis of ciprofloxacin pivotal trial

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Recruitment to ciprofloxacin pivotal trial

3.10

Validation of trial authorisation by all relevant bodies in each centre

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Validation of the ciprofloxacin PIP by EMEA

3.8

Protocol ready for submission of the ciprofloxacin PIP to EMEA

3.7

Ciprofloxacin protocol validated by all partners and submitted to a peer-reviewed journal

3.6

Pilot Ciprofloxacin PK study report Month 18

3.5

Documents ready for scientific advice at EMEA

3.4

Ciprofloxacin summary of issues as programme reports and submissions to peer-reviewed journals

3.3

First patient recruited to registry

3.2

Ciprofloxacin registry set-up

3.1

WP3 Ciprofloxacin trial (Deliverables)

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3 Name of the institution Number

Partner information

Name of the scientific contact persons active in TINN Description of the organisation. Description of the laboratories involved within the organisation. Background and facilities Main tasks in the project per Work Package. Principal Investigators 2 4 5 5

WP Field of expertise Qualification Name

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Management of ethical issues within TINN

The research program in TINN includes

• preterm and term neonates a population of vulnerable, high risk

human subjects

• animal experiments in mice (Animal Experiments)
• 1. Co-ordination and Project Management team)
• International conventions and declarations
• EU legislation
• National regulations relevant to TINN research project
• 2. WP Ethics
• Human subjects and use of personal data
• Informed consent: Data protection issues
• 3. European Ethics Advisory Board (EAB)
• 4. Independent Safety Monitoring Board (ISMB)

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B.3.1 : Potential impacts

• 1.1 Impact on the Health and

Protection of European neonates

• 1.2 Impact on Good Clinical Practices

in neonatal drug evaluation

• 1.3 Scientific impact on European

Research

• 1.4 Educational Impact
• 1.5 Contribution to standards
• 1.6 Economic impact (SME)

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Governing Council (GC) Coordinator (COO) European Commission Executive Council (ExC) Workpackage Teams (WT) Project Management Team (PMT) Patient Advisory Board (PAB) Ethical Management Unit (EMU) Scientific Advisory Board (SAB)

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• 8 countries

16 partners (2 SMEs) 74 participants Score : 15.5/16 5 200 000 € 5 years

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