25 July 2013 EMA/CHMP/824715/2012 Committee for Medicinal Products for Human Use (CHMP) Assessment report Defitelio International non-proprietary name: Defibrotide Procedure No. EMEA/H/C/002393 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8613 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union Table of contents 1. Background information on the procedure .............................................. 8 1.1. Submission of the dossier ...................................................................................... 8 1.2. Manufacturers ...................................................................................................... 9 1.3. Steps taken for the assessment of the product ......................................................... 9 1.4. Steps taken for the re-examination procedure ....................................................... 10 2. Scientific discussion .............................................................................. 11 2.1. Introduction....................................................................................................... 11 2.2. Quality aspects .................................................................................................. 13 2.2.1. Introduction .................................................................................................... 13 2.2.2. Active Substance ............................................................................................. 13 2.2.3. Finished Medicinal Product ................................................................................ 15 2.2.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 17 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 17 2.2.6. Recommendation(s) for future quality development ............................................. 17 2.3. Non-clinical aspects ............................................................................................ 18 2.3.1. Introduction .................................................................................................... 18 2.3.2. Pharmacology ................................................................................................. 18 2.3.3. Pharmacokinetics............................................................................................. 20 2.3.4. Toxicology ...................................................................................................... 21 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 23 2.3.6. Discussion on non-clinical aspects...................................................................... 24 2.4. Clinical aspects .................................................................................................. 25 2.4.1. Introduction .................................................................................................... 25 2.4.2. Pharmacokinetics............................................................................................. 26 2.4.3. Pharmacodynamics .......................................................................................... 30 2.4.4. Discussion on clinical pharmacology ................................................................... 33 2.4.5. Conclusions on clinical pharmacology ................................................................. 33 2.5. Clinical efficacy .................................................................................................. 33 2.5.1. Dose response study(ies) ................................................................................. 34 2.5.2. Main study(ies) ............................................................................................... 37 2.5.3. Discussion on clinical efficacy ............................................................................ 71 2.5.4. Conclusions on the clinical efficacy ..................................................................... 73 2.6. Clinical safety .................................................................................................... 74 2.6.1. Discussion on clinical safety .............................................................................. 80 2.6.2. Conclusions on the clinical safety ....................................................................... 82 2.7. Pharmacovigilance .............................................................................................. 82 Assessment report EMA/CHMP/824715/2012 Page 2/135 3. Benefit-Risk Balance ............................................................................. 82 4. Recommendations ................................................................................. 88 5. Re-examination of the CHMP opinion of 21 March 2013 ........................ 89 5.1. Detailed grounds for re-examination submitted by the applicant .............................. 89 5.2. Additional expert consultation- Report from the Ad hoc expert group meeting ............ 96 5.2.1. Prevention indication ........................................................................................ 96 5.2.2. Treatment indication ........................................................................................ 96 5.3. Additional information provided by the applicant .................................................... 97 5.4. Discussion on grounds for re-examination ............................................................. 98 5.5. Pharmacovigilance ............................................................................................ 103 5.6. Risk Management Plan ...................................................................................... 103 6. Assessment Overview of the content of the RMP ................................ 104 6.1. Safety concerns ............................................................................................... 104 6.2. Risk minimisation measures for Defitelio ............................................................. 116 7. Other considerations by the CHMP on the RMP ................................... 125 7.1. Plans for post-authorisation efficacy studies ......................................................... 125 7.2. Part VI of the RMP (Summary of activities in the risk management plan) ................. 125 7.3. Published public summary of the RMP ................................................................. 125 8. Benefit-Risk Balance ........................................................................... 125 9. Recommendations following re-examination ...................................... 131 Assessment report EMA/CHMP/824715/2012 Page 3/135 List of abbreviations A Adenine AE Adverse Event ALL Acute Lymphocytic Leukemia AML Acute Myelogenous Leukemia API active pharmaceutical ingredient AP1 In 2006-05 study: all enrolled patients who received at least one dose of study drug and reported outcome at the time of interim analysis. AP2 In 2006-05 study: all enrolled patients who received at least one dose of study drug and who were transplanted AND met study 2005-01 entry criteria aPTT activated Partial Thromboplastin Time ATIII Antithrombin III ATG Anti-Thymocyte Globulin AUC Area Under Curve AV Atrio-ventricular BCNU Carmustine bpm Beats per minute BU Busulphan °C Grade Celsius C Cytosine CD Circular dichroism CFR Code of Federal Regulations cfu colony forming units CGE capillary gel electrophoresis CI Confidence Interval CL Clearance Cmax Maximum Observed Concentration CML Chronic Myeloid Leukemia CNS Central Nervous System CR Complete Response CRO Contract Research Organisation CrCl Creatinine Clearance CUP Compassionate Use Program CV Coefficient of Variation Cy Cyclophosphamide Da Daltons Day+21 21 Days Post Stem Cell Transplant Day+30 30 Days Post Stem Cell Transplant Day+100 100 Days Post Stem Cell Transplant Day+180 180 Days Post Stem Cell Transplant DF Defibrotide dL Deciliter d.m. dry material DNA deoxyribonucleic acid Assessment report EMA/CHMP/824715/2012 Page 4/135 Ds Double stranded EBMT European Group for Blood and Marrow Transplantation ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group equiv Equivalent ESI-MS Electron Spray Ionization Mass Spectroscopy FR Frosinone (Italian Province) G Guanine GFR Glomerular Filtration Rate GLP Good Laboratory Practice GVHD Graft Versus Host Disease HC Historical Control HL Hodgkin's lymphoma HPLC High Pressure Liquid Chromatography HPLC/UV High-Pressure Liquid Chromatography with Ultraviolet Detector HSCT Haematopoietic Stem Cell Transplant HP-SEC High-performance size exclusion chromatography IC50 Half Maximal Inhibitory Concentration IND Investigational New Drug IPC In-process control IRB Institutional Review Board ITT Intent-to-treat IU International Unit i.v. /IV Intravenous Kel Elimination rate constant K.F. Karl Fischer Kg Kilogram KM Kaplan-Meier LBB Left Bundle Branch Block LLOQ Lower Limit of Quantitation LPS lipopolysaccharide mcg/μg Microgram mg Milligram MI Myocardial Infarction mL Milliliter mm Millimeter MO Major Objection MoA Mechanism of action MOF Multi Organ Failure MRC Medical Review Committee ms millisecond mw Molecular weight N Number NA Not applicable NHL non-Hodgkin's lymphoma NMT not more than Assessment report EMA/CHMP/824715/2012 Page 5/135 NLT not