19 September 2019 EMA/CHMP/548703/2019 Committee for Medicinal Products for Human Use (CHMP) Assessment Report on extension(s) of marketing authorisation Remsima International non-proprietary name: infliximab Procedure No. EMEA/H/C/002576/X/0062 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 © European Medicines Agency, 2019. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure ............................................ 11 1.1. Submission of the dossier .................................................................................... 11 1.2. Steps taken for the assessment of the product ....................................................... 11 2. Scientific discussion .............................................................................. 12 2.1. Problem statement ............................................................................................. 12 2.2. About the product .............................................................................................. 13 2.3. Type of Application and aspects on development .................................................... 14 2.4. Quality aspects .................................................................................................. 14 2.4.1. Introduction .................................................................................................... 14 2.4.2. Active Substance ............................................................................................. 15 2.4.3. Finished Medicinal Product ................................................................................ 18 2.4.4. Discussion on chemical, pharmaceutical and biological aspects .............................. 21 2.4.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 21 2.4.6. Recommendation(s) for future quality development ............................................. 21 2.5. Non-clinical aspects ............................................................................................ 21 2.5.1. Introduction .................................................................................................... 21 2.5.2. Pharmacology ................................................................................................. 22 2.5.3. Pharmacokinetics............................................................................................. 22 2.5.4. Toxicology ...................................................................................................... 23 2.5.5. Ecotoxicity/environmental risk assessment ......................................................... 24 2.5.6. Discussion on non-clinical aspects...................................................................... 24 2.5.7. Conclusion on the non-clinical aspects ................................................................ 24 2.6. Clinical aspects .................................................................................................. 24 2.6.1. Introduction .................................................................................................... 24 2.6.2. Pharmacokinetics............................................................................................. 29 2.6.3. Pharmacodynamics .......................................................................................... 38 2.6.4. Discussion on clinical pharmacology ................................................................... 44 2.6.5. Conclusions on clinical pharmacology ................................................................. 46 2.7. Clinical efficacy .................................................................................................. 46 2.7.1. Dose-response studies ..................................................................................... 46 2.7.2. Main study ...................................................................................................... 59 2.7.3. Discussion on clinical efficacy ............................................................................ 80 2.7.4. Conclusions on clinical efficacy .......................................................................... 86 2.8. Clinical safety .................................................................................................... 86 2.8.1. Discussion on clinical safety ............................................................................ 129 2.8.2. Conclusions on clinical safety .......................................................................... 135 2.9. Risk Management Plan ...................................................................................... 136 2.10. Pharmacovigilance .......................................................................................... 139 2.11. Product information ........................................................................................ 139 2.11.1. User consultation ......................................................................................... 139 3. Benefit-Risk Balance............................................................................ 140 3.1. Therapeutic Context ......................................................................................... 140 3.1.1. Disease or condition ....................................................................................... 140 3.1.2. Available therapies and unmet medical need ..................................................... 140 Assessment Report on extension(s) of marketing authorisation EMA/CHMP/548703/2019 Page 2/150 3.1.3. Main clinical studies ....................................................................................... 140 3.2. Favourable effects ............................................................................................ 141 3.3. Uncertainties and limitations about favourable effects ........................................... 141 3.4. Unfavourable effects ......................................................................................... 142 3.5. Uncertainties and limitations about unfavourable effects ....................................... 143 3.6. Effects Table .................................................................................................... 144 3.7. Benefit-risk assessment and discussion ............................................................... 145 3.7.1. Importance of favourable and unfavourable effects ............................................ 146 3.7.2. Balance of benefits and risks ........................................................................... 148 3.7.3. Additional considerations on the benefit-risk balance ......................................... 148 3.8. Conclusions ..................................................................................................... 149 4. Recommendations ............................................................................... 149 Assessment Report on extension(s) of marketing authorisation EMA/CHMP/548703/2019 Page 3/150 List of abbreviations 6-MP 6-Mercaptopurine ACP Assay (screening) cut point ACR American College of Rheumatology ACR20 20% improvement according to the ACR criteria ACR50 50% improvement according to the ACR criteria ACR70 70% improvement according to the ACR criteria ADA Anti-drug antibodies ADCC Antibody-dependent cellular cytotoxicity ADR Adverse drug reaction AE Adverse event AESI Adverse events of special interest AI Auto-injector ALP Alkaline phosphatase ALT Alanine aminotransferase ANCOVA Analysis of covariance Anti-CCP Anti-cyclic citrullinated peptide AR Analytical recovery ARR Administration-related reaction AS Ankylosing spondylitis ASAS Assessment of spondyloarthritis international society score ASAS20 At least 20% improvement of Assessment of spondyloarthritis international society score AST Aspartate aminotransferase AUC Area under the concentration-time curve AUC0-672hr Area under the serum concentration-time curve from time zero to 672 hours AUC0-inf Area under the concentration-time curve from time zero to infinity AUC0-last Area under the concentration-time curve from time zero to the last quantifiable concentration AUC0-t Area under the serum concentration-time curve from time zero to the last quantifiable concentration AUC22-30wk Area under the curve from week 22 - 30 AUCextrap Area under the concentration-time curve extrapolated from time zero to infinity AUCss Area under the concentration-time curve at steady state AUCss8W Area under the concentration-time curve normalized to an 8-week interval, calculated over actual dosing interval AUCτ Area under the serum concentration time curves at steady state over the actual dosing interval calculated using the linear trapezoidal rule AUCextrap % Area under the concentration-time curve extrapolated from time zero to infinity as a percentage of total AUC AZA Azathioprine BA Bioavailability BASDAI Bath ankylosing spondylitis disease activity index BDAS28 Apparent zero-order rate constant for production of the response Assessment Report on extension(s) of marketing authorisation EMA/CHMP/548703/2019 Page 4/150 BE Bioequivalence BLQ Below the lower limit of quantification BMI Body