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Blectifor,INN-Caffeine Citrate 26 January 2017 EMA/CHMP/41570/2017 Committee for Medicinal Products for Human Use (CHMP) Withdrawal Assessment report Blectifor International non-proprietary name: caffeine citrate Procedure No. EMEA/H/C/004100 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2017. Reproduction is authorised provided the source is acknowledged. Table of contents Table of contents ......................................................................................... 2 List of abbreviations .................................................................................... 4 1. Recommendations ................................................................................... 6 2. Executive summary ................................................................................. 7 2.1. Problem statement ............................................................................................... 7 2.1.1. Disease or condition ........................................................................................... 7 2.1.2. Epidemiology .................................................................................................... 8 2.1.3. Aetiology and pathogenesis ................................................................................ 8 2.1.4. Clinical presentation, diagnosis prognosis ............................................................. 9 2.1.5. Management ..................................................................................................... 9 2.2. About the product .............................................................................................. 10 2.3. The development programme/compliance with CHMP guidance/scientific advice ......... 10 2.4. General comments on compliance with GMP, GLP, GCP ........................................... 10 2.5. Type of application and other comments on the submitted dossier............................ 11 3. Scientific overview and discussion ........................................................ 13 3.1. Quality aspects .................................................................................................. 13 3.1.1. Introduction .................................................................................................... 13 3.1.2. Active Substance ............................................................................................. 14 3.1.3. Finished Medicinal Product ................................................................................ 14 3.1.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 18 3.1.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 19 3.2. Non clinical aspects ............................................................................................ 20 3.2.1. Pharmacology ................................................................................................. 20 3.2.2. Pharmacokinetics............................................................................................. 20 3.2.3. Toxicology ...................................................................................................... 21 3.2.4. Ecotoxicity/environmental risk assessment ......................................................... 21 3.2.5. Discussion on non-clinical aspects...................................................................... 22 3.2.6. Conclusion on non-clinical aspects ..................................................................... 22 3.3. Clinical aspects .................................................................................................. 22 3.3.1. Pharmacokinetics............................................................................................. 28 3.3.2. Pharmacodynamics .......................................................................................... 31 3.3.3. Discussion on clinical pharmacology ................................................................... 32 3.3.4. Conclusions on clinical pharmacology ................................................................. 34 3.3.5. Clinical efficacy ............................................................................................... 35 3.3.6. Discussion on clinical efficacy ............................................................................ 43 3.3.7. Conclusions on clinical efficacy .......................................................................... 48 3.3.8. Clinical safety .................................................................................................. 48 3.3.9. Discussion on clinical safety .............................................................................. 56 3.3.10. Conclusions on clinical safety .......................................................................... 58 3.4. Risk management plan ........................................................................................ 58 3.5. Pharmacovigilance system ................................................................................... 62 Blectifor EMA/CHMP/41570/2017 Page 2/70 4. Orphan medicinal products .................................................................... 62 5. Benefit risk assessment ......................................................................... 62 5.1. Therapeutic Context ........................................................................................... 62 5.1.1. Disease or condition ......................................................................................... 62 5.1.2. Available therapies and unmet medical need ....................................................... 63 5.1.3. Main clinical studies ......................................................................................... 63 5.2. Favourable effects .............................................................................................. 63 5.3. Uncertainties and limitations about favourable effects ............................................. 64 5.4. Unfavourable effects ........................................................................................... 66 5.5. Uncertainties and limitations about unfavourable effects ......................................... 67 5.6. Effects Table ...................................................................................................... 68 5.7. Benefit-risk assessment and discussion ................................................................. 68 5.7.1. Importance of favourable and unfavourable effects .............................................. 68 5.7.2. Balance of benefits and risks ............................................................................. 69 5.7.3. Additional considerations on the benefit-risk balance ........................................... 70 5.8. Conclusions ....................................................................................................... 70 Blectifor EMA/CHMP/41570/2017 Page 3/70 List of abbreviations AP or AOP Apnoea of prematurity API Active Pharmaceutical Ingredient ARR adjusted risk ratio ASM Active Substance Manufacturer ASMF Active Substance Master File BBB blood-brain barrier BPD bronchopulmonary dysplasia CEP Certificate of Suitability of the EP CI confidence interval CNS central nervous system CoA Certificate of Analysis CPAP continuous positive airway pressure CVS cardiovascular system ET endotracheal FPM Finished Product Manufacturer GA gestational age IPC In-process control IVH intraventricular haemorrhage LT Less than MA Marketing Authorization MAH Marketing Authorisation Holder NEC necrotising enterocolitis NMT Not more than NNT number needed to treat OR odds ratio PCA post-conceptional age PD pharmacodynamic PDA patent ductus arteriosus Ph.Eur. European Pharmacopoeia PK pharmacokinetic Blectifor EMA/CHMP/41570/2017 Page 4/70 PMA post-menstrual age PNA post-natal age PPV positive pressure ventilation RCT randomised controlled trial RDS respiratory distress syndrome (= hyaline membrane disease of newborn) ROP retinopathy of prematurity RS respiratory system SD standard deviation VLBW very low birthweight WFI Water for Injections Blectifor EMA/CHMP/41570/2017 Page 5/70 1. Recommendations Based on the CHMP review of the data on quality, safety and efficacy, the CHMP considers that the application for Blectifor 10 mg/ml solution for injection and oral solution, an orphan medicinal product in prevention of bronchopulmonary dysplasia in preterm neonates is not approvable since "major objections" have been identified, which preclude a recommendation for marketing authorisation at the present time. The details of these major objections are provided in the preliminary list of questions (Section VI) The major objections precluding a recommendation of marketing authorisation pertain to the following principal deficiencies: Legal basis The applicant has not addressed all of the requirements for demonstration of the well-established use of caffeine (citrate) in BPD. Specifically, the systematic and documented use in the EU for the intended indication has not been sufficiently addressed so far. The applicant´s strategy for study search and inclusion in their qualitative synthesis should be explained and coherence of results between relevant
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