HET SAFE-PEDRUG PROJECT. Pauline De Bruyne Johan Vande Walle

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1 DE WEG NAAR WERKZAME EN VEILIGE GENEESMIDDELEN VOOR KINDEREN: HET SAFE-PEDRUG PROJECT Pauline De Bruyne Johan Vande Walle

2 CLINICAL CASE Boy, 9yrs old. Hypertension. Management: Reversible causes? Non pharmacological treatment Pharmacological treatment: lisinopril

3 CLINICAL CASE Guidelines: 0,08 0,6mg/kg once daily Approved for use in children > 6 years Prescription: lisinopril 2,5mg once daily

4 CLINICAL CASE Boy, 5 months old. Hypertension. Management: Reversible causes? Non pharmacological treatment Pharmacological treatment: lisinopril

5 CLINICAL CASE Guidelines: 0,08 0,6mg/kg once daily Approved for use in children > 6 years OFF-LABEL Prescription: 0,4mg once daily UNLICENSED

6 OFF-LABEL AND/OR UNLICENSED PRESCRIPTIONS 50% in general paediatrics Source: t Jong et al. Pediatrics 2001; 108: % in (neonatal) intensive care Source: Conroy et al. BMJ 2000; 320: 79-82

7 MARKETING AUTHORISATION: OLD TIMELINE Safety? Efficacy? Quality? ADULT Preclinical Phase 1 Phase 2 Phase 3 Submission and review MA Post approval (Phase 4) Laboratory tests Animal models PAEDIATRIC Healthy adults PIP process begins Adult patients PIP amendments PIP compliance or deferral or waiver Children Paediatric studies defined in deferral

8 ON-LABEL PRESCRIBING OFF-LABEL PRESCRIBING Cavalla, D (2015). Off-label prescribing: justifying unapproved medicine.

9 DOSE - EXPOSURE - RESPONSE Absorption Distribution Metabolism Excretion Dose PHARMACOKINETICS (PK) Exposure: Concentration PHARMACODYNAMICS (PD) Drug response Covariates such as disease, drugs, genetics and age

10 Bron: Kearns et al, N Engl J Med 2003; 349:

11 Metabolic capacity Integumentary development Distribution sites Renal function Gastrointestinal function Bron: Kearns et al, N Engl J Med 2003; 349:

12 Metabolic capacity Integumentary development Distribution sites Renal function Children are not small adults. Gastrointestinal function Bron: Kearns et al, N Engl J Med 2003; 349:

13 BURDEN OF PAEDIATRIC CLINICAL TRIALS Ethical issues High cost small market size Technical difficulties Heterogeneous group

14 PAEDIATRIC MEDICINES INITIATIVES US Voluntary Requirement FDA Modernisation Act (FDAMA) Best Pharmaceuticals for children Act (BPCA) Pediatric Research Equity Act (PREA) FDA Amendments Act (FDAAA) FDA Safety and Innovation Act (FDASIA) EU Requirement Development process leading to EU Paediatric regulation coming into force EU Paediatric regulation

15 PAEDIATRIC REGULATION Paediatric Regulation (2007) Trigger New drug, new indication, new formulation, new route of administration Off-patent medicine Orphan Medicine (for rare disease in 5 / persons) Development Mandatory Voluntary Mandatory Instrument Paediatric Investigation Plan (PIP) Reward 6 months SPC extension 10 years of data protection (PUMA) 2 additional years of market exclusivity

16 DRUG DEVELOPMENT: OLD TIMELINE ADULT Preclinical Phase 1 Phase 2 Phase 3 Submission and review MA Post approval (Phase 4) PAEDIATRIC PIP process begins PIP amendments PIP compliance or deferral or waiver Children Paediatric studies defined in deferral

17 DRUG DEVELOPMENT: PAEDIATRIC REGULATION ADULT Preclinical Phase 1 Phase 2 Phase 3 Submission and review MA Post approval (Phase 4) PAEDIATRIC PIP process begins Paediatric Investigational Plan (PIP) PIP amendments Paediatric studies PIP compliance PIP or deferral or waiver compliance check or waiver or deferral Paediatric studies defined in deferral Paediatric studies defined in deferral

18 GENERAL CONCLUSION: GAPS Information on: Pharmacokinetics Efficacy (Long term) safety Secondary paediatric indications Paediatric formulations Rational use of medicines

19 DRUG DEVELOPMENT: NEW TIMELINE ADULT Preclinical Phase 1 Phase 2 Phase 3 Submission and review MA Post approval (Phase 4) PAEDIATRIC PIP process begins Paediatric Investigational Plan (PIP) PIP amendments Paediatric studies PIP compliance check or waiver or deferral PIP compliance or deferral or waiver Paediatric studies defined in deferral Paediatric studies defined in deferral Preclinical techniques: Modelling & simulation Predictive animal models Critical selection of compounds Pharmacovigilance Clinical trial transparency Honest post-study marketing

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21 Paediatric clinical trials Juvenile animal models PK/PD modelling Ethics of clinical trials Knowledge on paediatric PK/PD Trials in critically ill children Neonatal trials

22 Paediatric Faculty of Medicine and clinical trials health sciences Faculty of Juvenile animal Veterinary models Medicine Faculty PK/PD of modelling Pharmaceutical sciences Faculty Ethicsof of Arts clinical and Philosophy trials Knowledge on paediatric PK/PD Trials Faculty in of critically Medicine and ill children Health sciences Faculty of Medicine Neonatal trials

23 Paediatric clinical trials Juvenile animal models PK/PD modelling Ethics of clinical trials Knowledge on paediatric PK/PD Trials in critically ill children Neonatal trials

24 Paediatric clinical trials Juvenile animal models PK/PD modelling Ethics of clinical trials Knowledge on paediatric PK/PD Trials in critically ill children Neonatal trials

25 20 18 MELT Tablet 200µg tablet ~ 120µg MELT? ddavp plasma concentration (pg/ml) hour post dosing 2 hours post dosing 6 hours post dosing Time post dosing

26 MODELLING AND SIMULATION

27 MODELLING AND SIMULATION

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29 MODELLING AND SIMULATION

30 NETWORKING AND COLLABORATION Patient and their families / patient organizations Institutional Review Boards Regulatory Authorities Industry Academia Child health professionals Government and funding agencies

31 REVERSED SCIENCE CAFÉ

32 FUTURE PERSPECTIVES Paediatric Clinical Trial Unit & Paediatric Clinical Research Center In collaboration with and.

33 IMI2, Call 10, Topic 4: Creation of a pan-european paediatric clinical trials network

34 Daphné Christiaens Fien Dewolf Anca Amza Johan Vande Walle Ann Raes Peter De Paepe Pieter De Cock Pauline De Bruyne Lien Dossche Sofie Bekaert Lieve Nuytinck Jan Van Bocxlaer An Vermeulen Robin Michelet Violeta Balbas Martinez Yvan Vandenplas Reiner Mauel Kevin Meesters Siska Croubels Mathias Devreese Elke Gasthuys Karel Allegaert Anne Smits Anke Raaijmakers Freddy Mortier Wannes Van Hoof