30 January 2020 EMA/92635/2020 Committee for Medicinal Products for Human Use (CHMP) Assessment report Cinacalcet Accordpharma International non-proprietary name: cinacalcet Procedure No. EMEA/H/C/005236/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Downloaded from wizmed.com Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 7 1.1. Submission of the dossier ...................................................................................... 7 1.2. Steps taken for the assessment of the product ......................................................... 9 2. Scientific discussion .............................................................................. 10 2.1. Introduction....................................................................................................... 10 2.1.1. Problem statement .......................................................................................... 10 2.1.2. About the product ............................................................................................ 10 2.1.3. The development programme/compliance with CHMP guidance/scientific advice ...... 11 2.2. Quality aspects .................................................................................................. 11 2.2.1. Introduction .................................................................................................... 11 2.2.2. Active Substance ............................................................................................. 11 General Information .............................................................................................. 11 Manufacture, process controls and characterisation .............................................. 12 Stability ................................................................................................................. 14 2.2.3. Finished Medicinal Product ................................................................................ 14 Description of the product and Pharmaceutical Development ................................. 14 Product specification, analytical procedures, batch analysis .................................. 17 Adventitious agents ............................................................................................... 18 2.2.4. Discussion on chemical, and pharmaceutical aspects ............................................ 18 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 18 2.2.6. Recommendations for future quality development................................................ 18 2.3. Non-clinical aspects ............................................................................................ 19 2.3.1. Introduction .................................................................................................... 19 2.3.2. Ecotoxicity/environmental risk assessment ......................................................... 19 2.3.3. Discussion on non-clinical aspectsDownloaded................................ from wizmed.com ...................................... 19 2.3.4. Conclusion on non-clinical aspects ..................................................................... 19 2.4. Clinical aspects .................................................................................................. 19 2.4.1. Introduction .................................................................................................... 19 2.4.2. Pharmacokinetics............................................................................................. 21 Methods .................................................................................................................. 21 Study design ............................................................................................................ 21 Test and reference products ....................................................................................... 22 Population(s) studied ................................................................................................ 22 Analytical methods .................................................................................................... 24 Pharmacokinetic Variables.......................................................................................... 24 Statistical methods ................................................................................................... 24 Results .................................................................................................................... 25 Safety data .............................................................................................................. 27 2.4.3. Pharmacokinetic Conclusion .............................................................................. 28 2.4.4. Pharmacodynamics .......................................................................................... 28 2.4.5. Post-marketing experience ............................................................................... 28 2.4.6. Discussion on clinical aspects ............................................................................ 29 Assessment report EMA/92635/2020 Page 2/33 2.4.7. Conclusions on clinical aspects .......................................................................... 29 2.5. Risk Management Plan ........................................................................................ 29 2.6. Pharmacovigilance .............................................................................................. 31 2.7. Product information ............................................................................................ 31 2.7.1. User consultation ............................................................................................. 31 3. Benefit-Risk Balance.............................................................................. 31 4. Recommendations ................................................................................. 31 Downloaded from wizmed.com Assessment report EMA/92635/2020 Page 3/33 List of abbreviations AAS: Atomic Absorption Spectrometry AE Adverse event ANIOVA Analysis of variances AP: Applicant's Part (or Open Part) of a ASMF API: Active Pharmaceutical Ingredient AR: Assessment Report AS: Active substance ASM: Active Substance Manufacturer ASMF: Active Substance Master File ATC Anatomical therapeutic chemical (classification system) AUC Area under the plasma concentration versus time curve BCS: Biopharmaceutics classification system BE: Bioequivalence BE Guideline: Guideline on the Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 01 – January 2010) BMD Bone mineral density BQL: Below quantification limit BSE: Bovine spongiform encephalopathy Ca Calcium Ca x P Calcium-phosphorus product CAC Coronary artery calcification CaR Calcium-sensing receptor CFU: Colony-forming unit CI Confidence interval CKD Chronic kidney disease Downloaded from wizmed.com CLcr Creatinine clearance Cmax Maximal (peak) plasma concentration CoA: Certificate of analysis CV Coefficient of variation CYP Cytochrome P450 DPM: Drug Product Manufacturer DSC: Differential scanning calorimetry EC50 Effective concentration 50% EMA European Medicines Agency ESRD End-stage renal disease EU European Union EU: European Union Fct: Film coated tablet FDA Food and Drug Administration FGF Fibroblast growth factor Assessment report EMA/92635/2020 Page 4/33 FHH Familial hypocalciuric hypocalcaemia GC Gas chromatography GCP Good Clinical Practice GFR glomerular filtration rate GMP: Good Manufacturing Practice GVP Good Pharmacovigilance Practice HCL Hydrochloride HDPE: High Density Polyethylene HIV Human immunodeficiency virus HPLC: High Performance Liquid Chromatography HPT Hyperparathyroidism HR hazard ratio IC50 Inhibitory concentration 50% ICH: International Conference on Harmonisation INN International Nonproprietary Name IPC: In-process controls iPTH Intact parathyroid hormone IR: Infra-Red Spectroscopy IV intravenous(ly) JECFA: Joint Evaluation Committee on Food Additives JP MO: Japanese Ministerial Ordinance JPE: Japanese Pharmaceutical Excipients KDOQI Kidney Disease Outcome Quality Initiative Kel Elimination constant LDPE: Low Density Polyethylene LOD: Limit of Detection Downloaded from wizmed.com LOQ: Limit of Quantitation LoQ: List of Questions LSmean Least square mean MAH marketing authorization holder MAPK Mitogen-activated protein kinase MedDRA Medical Dictionary for Regulatory Activities N/A Not applicable ND: Not detected NLT: Not Less Than NMR: Nuclear Magnetic Resonance NMT Not More Than P Phosphorus PD peritoneal dialysis PE: Polyethylene Ph.Eur. European Pharmacopoeia Assessment report EMA/92635/2020 Page 5/33 PIL: Patient Information Leaflet PP: Polypropylene primary HPT primary hyperparathyroidism pmarp per million of the age-related population pmp per million population PRT post-renal transplant PSUR periodic safety update report PTH parathyroid hormone PY patient years PVC: Poly vinyl chloride QOS: Quality Overall Summary QP: Qualified Person QPPV Qualified Person for Pharmacovigilance