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Veklury: Assessment Report 25 June 2020 EMA/357513/2020 Committee for Medicinal Products for Human Use (CHMP) Assessment report Veklury International non-proprietary name: remdesivir Procedure No. EMEA/H/C/005622/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 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 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 ........................................................ 8 2. Scientific discussion ................................................................................ 9 2.1. Problem statement ............................................................................................... 9 2.1.1. Disease or condition .......................................................................................... 9 2.1.2. Epidemiology .................................................................................................. 10 2.1.3. Biologic features, aetiology and pathogenesis ..................................................... 11 2.1.4. Clinical presentation, diagnosis ......................................................................... 11 2.1.5. Management .................................................................................................. 12 2.2. Quality aspects .................................................................................................. 14 2.2.1. Introduction ................................................................................................... 14 2.2.2. Active Substance ............................................................................................ 14 2.2.3. Finished Medicinal Product................................................................................ 18 2.2.4. Discussion on chemical, pharmaceutical and biological aspects ............................. 29 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 30 2.2.6. Recommendations for future quality development ............................................... 32 2.3. Non-clinical aspects ............................................................................................ 34 2.3.1. Introduction ................................................................................................... 34 2.3.2. Pharmacology ................................................................................................. 34 2.3.3. Pharmacokinetics ............................................................................................ 35 2.3.4. Toxicology ...................................................................................................... 39 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 43 2.3.6. Discussion on non-clinical aspects ..................................................................... 44 2.3.7. Conclusion on the non-clinical aspects ............................................................... 46 2.4. Clinical aspects .................................................................................................. 47 2.4.1. Introduction ................................................................................................... 47 2.4.2. Pharmacokinetics ............................................................................................ 50 2.4.3. Pharmacodynamics ......................................................................................... 62 2.4.4. Discussion on clinical pharmacology .................................................................. 71 2.4.5. Conclusions on clinical pharmacology................................................................. 78 2.5. Clinical efficacy .................................................................................................. 82 2.5.1. Dose response studies ..................................................................................... 82 2.5.2. Main studies ................................................................................................... 83 2.5.3. Discussion on clinical efficacy .......................................................................... 119 2.5.4. Conclusions on the clinical efficacy ................................................................... 122 2.6. Clinical safety ................................................................................................... 123 2.6.1. Discussion on clinical safety ............................................................................ 154 2.6.2. Conclusions on the clinical safety ..................................................................... 156 2.7. Risk Management Plan....................................................................................... 156 2.8. Pharmacovigilance ............................................................................................ 160 2.9. New Active Substance ....................................................................................... 160 2.10. Product information ......................................................................................... 160 2.10.1. User consultation ......................................................................................... 160 Assessment report EMA/357513/2020 Page 2/199 2.10.2. Labelling exemptions .................................................................................... 160 2.10.3. Quick Response (QR) code ............................................................................ 161 2.10.4. Additional monitoring .................................................................................... 161 3. Benefit-Risk Balance............................................................................ 162 3.1. Therapeutic Context .......................................................................................... 162 3.1.1. Disease or condition ....................................................................................... 162 3.1.2. Available therapies and unmet medical need ..................................................... 162 3.1.3. Main clinical studies ........................................................................................ 162 3.2. Favourable effects ............................................................................................. 163 3.3. Uncertainties and limitations about favourable effects ........................................... 164 3.4. Unfavourable effects ......................................................................................... 165 3.5. Uncertainties and limitations about unfavourable effects ........................................ 166 3.6. Effects Table .................................................................................................... 168 3.7. Benefit-risk assessment and discussion ............................................................... 170 3.7.1. Importance of favourable and unfavourable effects ............................................ 170 3.7.2. Balance of benefits and risks ........................................................................... 170 3.7.3. Additional considerations on the benefit-risk balance .......................................... 171 3.8. Conclusions ...................................................................................................... 171 4. Recommendations ............................................................................... 172 Appendix ................................................................................................................ 176 Assessment report EMA/357513/2020 Page 3/199 List of abbreviations AAS Atomic Absorption Spectrometry AP Applicant's Part (or Open Part) of an ASMF RDV Remdesivir RP Restricted Part (or Closed Part) of an ASMF API Active Pharmaceutical Ingredient ASM Active Substance Manufacturer ASMF Active Substance Master File CA Competent Authority CFU Colony Forming Units CMA Conditional Marketing Authorization CMS Concerned Member State CoA Certificate of Analysis CQA critical quality attribute CRS Chemical Reference Substance (official standard) COVID-19 Coronavirus disease 2019 DS Drug Substance DSC differential scanning calorimetry DSM Drug Substance Manufacturer DP Drug Product DPM Drug Product Manufacturer DSC Differential Scanning Calorimetry ECMO Extracorporeal membrane oxygenation EDQM European Directorate for the Quality of Medicines GC gas chromatography GMP Good Manufacturing Practice HDPE High Density Polyethylene ICH International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use ICP Inductively Coupled Plasma IPC In-Process Control IR Infrared (spectroscopy) Assessment report EMA/357513/2020 Page 4/199 IU International Units LDPE Low Density Polyethylene LOA Letter of Access LOD Limit of Detection LOQ Limit of Quantitation LoQ List of Questions LT Less Than MAH Marketing Authorisation Holder MDD maximum daily dose MS Mass Spectrometry MV Mechanically ventilated ND Not Detected NLT Not Less Than NMR Nuclear Magnetic Resonance NMT Not More Than OES Optical Emission
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