COVID-19 Vaccine AstraZeneca - European Medicines Agency

1 Official address Domenico Scarlattilaan 6 1083 HS Amsterdam The Netherlands An Agency of the European Union Address for visits and deliveries Refer to Send us a question Go to Telephone +31 (0)88 781 6000 European Medicines Agency , 2021. Reproduction is authorised provided the source is acknowledged. 29 January 2021 EMA/94907/2021 Committee for Medicinal Products for Human Use (CHMP) assessment report COVID-19 Vaccine AstraZeneca Common name: COVID-19 Vaccine (ChAdOx1-S [recombinant]) Procedure No. EMEA/H/C/005675/0000 Note assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted.

2 EMA/94907/2021 Page 2/181 Table of contents 1. Background information on the procedure .. 7 Submission of the dossier .. 7 Steps taken for the assessment of the product .. 9 2. Scientific discussion .. 12 Problem statement .. 12 Disease or condition .. 12 Epidemiology and risk factors .. 12 Aetiology and pathogenesis .. 12 Clinical presentation and diagnosis .. 13 Management .. 13 Quality aspects .. 15 15 Active substance .. 15 Finished medicinal product .. 25 Discussion on chemical, and pharmaceutical aspects.

3 35 Conclusions on the chemical, pharmaceutical and biological aspects .. 39 Recommendations for future quality development .. 41 Non-clinical aspects .. 42 Pharmacology .. 42 Pharmacokinetics .. 46 Toxicology .. 47 Ecotoxicity/environmental risk assessment .. 49 Discussion on non-clinical aspects .. 49 Conclusion on the non-clinical aspects .. 54 Clinical aspects .. 54 54 Pharmacokinetics .. 59 Pharmacodynamics .. 59 Discussion on clinical pharmacology .. 71 Conclusions on clinical pharmacology .. 73 Clinical efficacy.

4 73 Main studies .. 74 Pooled efficacy analysis .. 77 Discussion on clinical efficacy .. 115 Conclusions on clinical efficacy .. 123 Clinical safety .. 124 Methodology .. 124 Patient exposure .. 124 Adverse events .. 125 Serious adverse event/deaths/other significant events .. 135 EMA/94907/2021 Page 3/181 Laboratory findings .. 136 Safety in special populations .. 137 Immunological events .. 137 Safety related to drug-drug interactions and other interactions .. 137 Discontinuation due to adverse events .. 138 Post marketing experience.

5 138 Discussion on clinical safety .. 138 Conclusions on the clinical safety .. 141 Risk Management Plan .. 142 Safety concerns .. 142 Pharmacovigilance plan .. 144 Risk minimisation 154 Routine Risk Minimisation Measures .. 154 Summary of additional risk minimisation measures .. 154 Pharmacovigilance .. 157 Pharmacovigilance system .. 157 Periodic Safety Update Reports submission requirements .. 158 New Active Substance .. 158 Product information .. 158 User consultation .. 158 Labelling exemptions .. 158 Quick Response (QR) code.

6 161 Additional monitoring .. 161 Compliance with scientific advice .. 161 3. Benefit-Risk Balance .. 162 Disease .. 162 Available therapies and unmet medical need .. 162 Main clinical studies .. 162 Favourable effects .. 163 Uncertainties and limitations about favourable effects .. 164 Unfavourable effects .. 166 Uncertainties and limitations about unfavourable effects .. 168 Effects Table .. 169 Benefit-risk assessment and discussion .. 171 Importance of favourable and unfavourable effects .. 171 Balance of benefits and risks.

7 172 Additional considerations on the benefit-risk balance .. 172 Conditional marketing authorisation .. 173 Conclusions .. 174 4. Recommendations .. 174 EMA/94907/2021 Page 4/181 List of abbreviations ACE-2 Angiotensin-Converting Enzyme 2 ADE Antibody-Dependent Enhancement AdHu Human Adenovirus ADME Absorption, distribution, metabolism, excretion AEX Anion exchange chromatography ARDS Acute respiratory distress syndrome AS Active substance AUC Analytical ultracentrifugation - AZD1222 COVID-19 Vaccine AstraZeneca BAL Bronchoalveolar Lavage BMI Body mass index BVH Bulk viral harvest BWP Biological Working Party ChAd63 Chimpanzee Adenovirus 63 ChAdOx1 Chimpanzee Adenovirus Ox1 ChAdOx1 MERS Chimpanzee Adenovirus Ox1 with MERS Spike antigen ChAdOx1 nCoV-19 Name of AZD1222 when initially developed by the University of Oxford ChAdOx2 Chimpanzee

8 Adenovirus Ox2 CHMP Committee for Medicinal Products for Human Use CMV Cytomegalovirus CNS Central Nervous System COVID-19 Coronavirus disease-2019 CPP Critical process parameter CQAs Critical quality attributes CT Computerised Tomography DART Developmental and Reproductive Toxicology DPP4 Dipeptidyl Peptidase 4 EC European Commission ECDC European Centre for Disease Prevention and Control EDTA Edetate disodium ELISA Enzyme-Linked Immunosorbent Assay ELISPOT Enzyme-Linked Immunospot EMA European Medicines Agency ERA Environmental Risk assessment ERD enhanced respiratory disease EU European Union FFF Field flow fractionation FIH First in Human FP Fi nished product g Guide GalK Galactokinase GFP Green Fluorescent Protein GI Gastrointestinal GLP Good Laboratory Practice GM Geometric Mean GMP Good Manufacturing Practice HAdV Human Adenovirus HAdV5 Human adenovirus serotype 5 HBV Hepatitis B virus HCP Host cell protein HEK Human Embryonic Kidney Cells HIV Human

9 Immunodeficiency Virus HRP Horseradish peroxidase ICH International Council for Harmonisation ICU Intensive care Unit IFN Interferon gamma IgG Immunoglobulin G EMA/94907/2021 Page 5/181 IL Interleukin IM Intramuscular IN Intranasal Infectious units IPC In-process controls LTCF Long-term care facilities MAA Marketing Authorisation Application MALS Multi-angle light scattering MC Microbial control MC Microbial Control MERS Middle East Respiratory Syndrome MERS-CoV Middle East Respiratory Syndrome Coronavirus ME-TRAP Multiple epitopes and thrombospondin related adhesion protein MHCB Master Host Cell Bank MHRA Medicines and Health products Regulatory Agency MVA Modified vaccinia virus Ankara MVM Minute virus of mice MVS Master virus seed NAb Neutralising antibody NAT Nucleic acid test NCPP Non-critical process parameter NHP Non-Human Primate NOAEL No-observed-adverse-effect level NP Influenza A nucleoprotein NTA Nanoparticle tracking analysis OC Other concern PA Performance attribute

10 PBMC Peripheral blood mononuclear cells PBS Phosphate-buffered saline PCR Polymerase chain reaction PCR Polymerase chain reaction PD Pharmacodynamic PDCO Paediatric Committee PFU Plaque-forming units Ph. Eur. European Pharmacopeia PIP Paediatric Investigation Plan PPQ Process performance qualification PRAC Pharmacovigilance Risk assessment Committee QC Quality control qPCR Quantitative polymerase chain reaction RBD Receptor-binding domain RCA Replication competent adenoviruses RMP Risk Management Plan RNA Ribonucleic acid RR Rolling review RT-PCR Reverse transcription polymerase chain reaction S surface Spike glycoprotein SAdV Simian Adenoviruses SAP Statistical Analysis Plan SARS-CoV-2 Severe Acute