Kiri

Saatja: [email protected] Saaja: [email protected], "EDQM SARE-TC" <[email protected]> Teema: Preliminary results on SARE TC 2023 (2022 data) exercise Kuupäev: 2023-12-14 15:02 Dear competent authorities for tissues and cells, Please find attached the preliminary results of the SARE exercise on TC 2023 (data 2022). We would appreciate if you could take a look and provide us your feedback on the data accuracy and the way of its interpretation until 19th January 2024. Please do not hesitate to contact us or directly EDQM (in copy) for any question or doubt. Many thanks and kind regards, The SoHO team. European Commission DG SANTE (Health and Food Safety) Unit D2 – Medical Products: quality, safety, innovation Office address: Rue Breydel 2, 06/004, B-1049 Brussels/Belgium <http://ec.europa.eu/health/blood_tissues_organs/policy/index_en.htm> http://ec.europa.eu/health/blood_tissues_organs/policy/index_en.htm THE EUROPEAN DIRECTORATE FOR THE QUALITY OF MEDICINES & HEALTHCARE (EDQM)  2023 SARE Exercise (2022 data) SARE Reporting for Tissues and Cells SoHO Standard Section, Department of Biological Standardization, OMCL Network & HealthCare (DBO) EDQM, Council of Europe ©2023 EDQM, Council of Europe. All rights reserved. 2 Reporting Countries 2023 SARE Exercise (2022 data) DATA COLLECTED from 30* Countries: AT, BE, BG, CY, CZ, DE, DK, EE, EL, ES, FI, FR, HR, HU, IS, IE, IT, LV, LI, LT, LU, MT, NL, NO, PL, PT, RO, SI, SK, SE and UK (Northern Ireland). • 2021 SARE exercise: 28 reporting countries • 2022 SARE exercise: 29 reporting countries • 2023 SARE exercise: 30 reporting countries (same as in 2022 + CY) *26 Member States + 4 Non-Member States ©2023 EDQM, Council of Europe. All rights reserved. 3 Summary 2023 SARE Exercise (2022 data) 2020 2021 2022 2023 Parameter (data 2019) (data 2020) (data 2021) (data 2022) Countries Countries Number Countries Number Countries Number Number reporting reporting reporting reporting T&C Units 26 2 922 117 24 2 646 079 25 3 159 362 27 2,892,459 Processed T&C Units 27 1 360 315 26 1 116 519 28 1 192 203 29 957,775 Distributed Transplant 22 298 897 19 245 058 24 318 467 26 327,961 Recipients SAR 18 306 18 350 19 326 17 347 Fatalities in - - 7 16 6 20 3 12 Recipients SAE 20 949 22 910 23 694 22 1133 SAR in 17 903 19 846 17 795 19 777 donors NOTE: FI and AT identified very minor discrepancies in the data regarding skeletal tissues & other tissues (amniotic membrane), and HSC respectively. Due to negligible impact on the SARE analysis and late communication, initial data reported was considered in the analysis. ©2023 EDQM, Council of Europe. All rights reserved. 4  2023 SARE Exercise (2022 data) Number of Reporting Countries by Sub-category of T&C Replacement T&C Parameter Skeletal CV Ocular Skin Other Tissues Tissues Tissues # of Distributed T&C 27 21 28 13 20 # of Recipients 17 16 23 10 16 # of Processed T&C 21 17 22 9 16 HSC Parameter General Bone PBSC Cord DLI Other HPC Marrow Blood # of Distributed T&C 2 18 19 5 13 5 # of Recipients 2 18 16 6 10 4 # of Processed T&C 2 16 16 14 12 4 Reproductive T&C Parameter Embryos Sperm Other Reproductive Cells # of Distributed T&C 19 19 13 # of Recipients 19 18 10 # of Processed T&C 15 17 12 ©2023 EDQM, Council of Europe. All rights reserved. 5  2023 Incidence of replacement T&C (distributed & recipients pmp*)SARE Exercise (2022 data) 0 200 400 600 800 1000 1200 1400 1600 1800 2000 Austria (AT) 1024 78 Belgium (BE) 1935 Bulgaria (BG) 118 80 Croatia (HR) 162 129 Cyprus (CY) 202 202 Czechia (CZ) 892 19 Denmark (DK) 657 547 Estonia (EE) 721 320 Finland (FI) 478 358 France (FR) 1684 1214 Germany (DE) 1079 Greece (EL) 1694 1398 Hungary (HU) 94 26 Ireland (IE) 157 146 Italy (IT) 444 Latvia (LV) 35 Lithuania (LT) 59 59 Luxembourg (LU) 1590 Malta (MT) 11.5 11 Netherlands (NL) 1132 487 Norway (NO) 541 200 Poland (PL) 974 Portugal (PT) 127 116 Romania (RO) 23 2 Slovenia (SI) 244 153 Spain (ES) 818 629 Sweden (SE) 279 230 UK (NI) 186 225 Incidence by Distributed pmp Incidence by Recipients pmp population on January 1st 2022, https://ec.europa.eu/eurostat/web/population-demography/demography-population-stock-balance/database * https://www.nisra.gov.uk/publications/2022-mid-year-population-estimates-northern-ireland (Due to Brexit, UK = Northern Ireland only) ©2023 EDQM, Council of Europe. All rights reserved. 6 Incidence of HSC (distributed & recipients pmp) 2023 SARE Exercise (2022 data) 0 100 200 300 400 500 600 Austria (AT) 202 63 Belgium (BE) 206 Bulgaria (BG) 27 25 Croatia (HR) 198 71 Cyprus (CY) 118 118 Czechia (CZ) 131 80 Denmark (DK) 208 86 Estonia (EE) 98 1 Finland (FI) 139 65 France (FR) 70 Greece (EL) 48 42 Hungary (HU) 44 45 Iceland (IS) 77 32 Ireland (IE) 121 57 Italy (IT) 82 92 Lithuania (LT) 82 82 Netherlands (NL) 282 105 Norway (NO) 47 40 Poland (PL) 609 Portugal (PT) 55 31 Romania (RO) 18 Slovenia (SI) 242 79 Spain (ES) 76 Sweden (SE) 125 79 UK (NI) 2 1 Incidence by Distributed pmp Incidence by Recipients pmp population on January 1st 2021, https://ec.europa.eu/eurostat/web/population-demography/demography-population-stock-balance/database * https://www.nisra.gov.uk/publications/census-2021-table-lookups (Due to Brexit, UK = Northern Ireland only) ©2023 EDQM, Council of Europe. All rights reserved. 7  2023 SARE Exercise (2022 data) Incidence of reproductive (distributed & recipients pmp) 0 1000 2000 3000 4000 5000 6000 7000 Austria (AT) 2555 1316 Belgium (BE) 5192 Bulgaria (BG) 2900 1351 Croatia (HR) 2529 1603 Cyprus (CY) 1873 1873 Czechia (CZ) 5533 2517 Denmark (DK) 1114 2976 Estonia (EE) 2332 1588 Finland (FI) 814 1099 Germany (DE) 1663 Hungary (HU) 2999 269 Iceland (IS) 2238 2238 Ireland (IE) 2066 1414 Latvia (LV) 1565 Liechtenstein (LI) 7199 Lithuania (LT) 793 792 Luxembourg (LU) 2969 1475 Malta (MT) 864 864 Netherlands (NL) 3388 1601 Norway (NO) 180 Portugal (PT) 1273 Romania (RO) 1874 Slovenia (SI) 7344 2213 Sweden (SE) 2053 1242 UK (NI) 1066 Incidence by Distributed pmp Incidence by Recipients pmp population on January 1st 2021, https://ec.europa.eu/eurostat/web/population-demography/demography-population-stock-balance/database * https://www.nisra.gov.uk/publications/census-2021-table-lookups (Due to Brexit, UK = Northern Ireland only) ©2023 EDQM, Council of Europe. All rights reserved. 8  2023 SARE Exercise (2022 data) Denominators ©2023 EDQM, Council of Europe. All rights reserved. 9  2023 SARE Exercise (2022 data) Denominators and total number of SAR by Year (2010 - 2022) 500 2,102,332 2,133,341 450 2,000,000 460 400 350 1,490,453 1,500,926 1,500,000 347 350 1,314,512 326 300 307 1,165,510 1,192,203 995,407 250 991,538 1,000,693 1,000,000 246 957,775 231 238 221 200 203 711,061 190 150 156 500,000 138 377,023 365,060 361,418 379,761 100 329,490 333,253 321,618 340,582 318,467 327,961 300,857 177,538 209,243 50 111,025 0 0 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 Number Distributed Number Recipients Number SAR ©2023 EDQM, Council of Europe. All rights reserved. 10 Denominators by Country 2023 SARE Exercise (2022 data) Replacement T&C N = 405 055 (distributed)* 0 20,000 40,000 60,000 80,000 100,000 Austria (AT) 9,199 Belgium (BE) 705 22,478 TC Distributed Number Recipients N = 149 823 (recipients)* Bulgaria (BG) 805 546 Croatia (HR) 626 500 Cyprus (CY) 183 183 Czechia (CZ) 9,382 200 Denmark (DK) 3,862 3,216 Estonia (EE) 961 426 Finland (FI) 2,651 1,989 France (FR) 114,322 82,372 Germany (DE) 89,791 Greece (EL) 17,720 14,629 Hungary (HU) 916 257 Ireland (IE) 796 741 Italy (IT) 26,212 Latvia (LV) 66 Lithuania (LT) 167 167 Luxembourg (LU) 1,026 Malta (MT) 6 6 Netherlands (NL) 19,920 8,574 Norway (NO) 2,933 1,086 Poland (PL) 36,678 Portugal (PT) 1,319 1,204 Romania (RO) 436 42 Slovenia (SI) 515 323 Spain (ES) 38,826 29,818 Sweden (SE) 2,904 2,408 UK (NI) 355 431 *Partial data (only number of T&C distributed or only number of recipients) was provided (BE, IT, LV, PL); no data was available at the time of reporting (IS, LI); data is not collected (DE). ©2023 EDQM, Council of Europe. All rights reserved. 11 Denominators by Country 2023 SARE Exercise (2022 data) Hematopoietic Stem Cells (HSC) TC Distributed Number Recipients 0 5,000 10,000 15,000 20,000 Austria (AT) 1,818 563 2,397 Belgium (BE) Bulgaria (BG) 183 N= 46 291 (distributed)* 175 Croatia (HR) 766 276 Cyprus (CY) Czechia (CZ) 107 107 1,382 N= 21 487 (recipients)* 847 Denmark (DK) 1,222 508 Estonia (EE) 131 1 Finland (FI) 771 359 France (FR) 4,784 Greece (EL) 508 445 Hungary (HU) 426 434 Iceland (IS) 29 12 Ireland (IE) 615 288 Italy (IT) 4,830 5,441 Lithuania (LT) 229 229 Netherlands (NL) 4,971 1,857 Norway (NO) 255 217 Poland (PL) 22,923 Portugal (PT) 566 325 Romania (RO) 345 Slovenia (SI) 510 166 Spain (ES) 3,630 Sweden (SE) 1,303 822 UK (NI) 4 1 *Partial data (only number of T&C distributed or only number of recipients) was provided (BE, ES, FR, PL, RO); no data was available at the time of reporting (LV); data is not collected (DE). ©2023 EDQM, Council of Europe. All rights reserved. 12  2023 SARE Exercise (2022 data) Reproductive T&C N= 506 429 (distributed)* TC Distributed Number Recipients 0 20,000 40,000 60,000 80,000 100,000 120,000 140,000 160,000 Austria (AT) Belgium (BE) 11,818 22,938 60,324 N= 156 651 (recipients)* Bulgaria (BG) 19,833 9,239 Croatia (HR) 9,767 6,190 Cyprus (CY) 1,695 1,695 Czechia (CZ) 58,190 26,472 Denmark (DK) 6,546 17,479 Estonia (EE) 3,106 2,115 Finland (FI) 4,518 6,100 Germany (DE) 138,431 Hungary (HU) 29,060 2,608 Iceland (IS) 842 842 Ireland (IE) 10,457 7,157 Latvia (LV) 2,936 Liechtenstein (LI) 283 Lithuania (LT) 2,224 2,224 Luxembourg (LU) 1,916 952 Malta (MT) 450 450 Netherlands (NL) 59,606 28,160 Norway (NO) 975 Portugal (PT) 13,180 Romania (RO) 35,683 Slovenia (SI) 15,474 4,664 Sweden (SE) 21,458 12,986 UK (NI) 2037 * Partial data (only number of T&C distributed or only number of recipients) was provided (BE, DE, LI, LV, PT, RO, UK(NI)). ©2023 EDQM, Council of Europe. All rights reserved. 13  2023 SARE Exercise (2022 data) Denominators: reporting countries Parameter Skeletal Tissues CV Tissues Ocular Tissues Skin Other 27 (23/2021) 21 (18/2021) 28 (24/2021) 12 (10/2021) 20 (18/2021) (AT, BE, BG, HR, CY, (AT, BE, HR, CZ, DK, (AT, BE, BG, HR, CY, (AT, CZ, EE, EL, ES, (AT, BE, BG, HR, CZ, Distributed CZ, DK, EE, EL, ES, EE, EL, ES, FI, FR, CZ, DK, EE, EL, ES, FI, IT, NL, PL, PT, DK, EE, EL, ES, FI, T&C FI, FR, DE, HU, IE, DE, HU, IE, IT, LT, FI, FR, DE, HU, IE, SI, and SE) FR, DE, IE, IT, LT, NL, IT, LV, LT, LU, NL, NL, NO, PL, PT, SI, IT, LV, LT, LU, MT, NO, PL, SI, and SE) NO, PL, PT, RO, SI, and SE) NL, NO, PL, PT, RO, SE, and UK(NI)) SI, SE, and UK(NI)) 17 (19/2021) 16 (13/2021) 23 (20/2021) 9 (10/2021) 16 (14/2021) (BG, HR, CY, DK, EE, (HR, CZ, DK, EE, EL, (AT, BG, HR, CY, DK, (EE, FI, EL, ES, NL, (AT, BG, HR, CZ, DK, Recipients EL, FI, FR, ES, IE, LT, ES, FI, FR, HU, IE, EE, EL, ES, FI, FR, NO, PT, SI, and EE, EL, ES, FI, FR, NL, NO, PT, SI, SE, LT, NL, NO, PT, SI, HU, IE, LT, LU, MT, SE) IE, LT, NL, NO, SI, and UK(NI)) and SE) NL, NO, PL, PT, RO, and SE) SI, SE, and UK(NI)) Note: Countries that reported “0” T&C are included. ©2023 EDQM, Council of Europe. All rights reserved. 14  2023 SARE Exercise (2022 data) Number of Distributed T&C by Sub-Category N = 405 055 Other tissues or cells 40,643 Skin 14,531 10% 3% Cardiovascular tissues 6,650 2% Ocular tissues 40,327 10% 2021 N= 391 687 Other Skin tissues or 20,413 cells 22,313 Skeletal tissues 302,904 Cardiovascular tissues 5% 6% 75% 6,430 2% Ocular tissues 30,858 8% Skeletal tissues 311,673 79% ©2023 EDQM, Council of Europe. All rights reserved. 15  2023 SARE Exercise (2022 data) Distributed Skeletal Tissues by Type N = 302 904 0 50,000 100,000 150,000 200,000 250,000 Bone 236,038 263,439 General skeletal tissues 46,417 28,635 Tendons/ligaments 7,418 6,203 Fascia 5,793 5,925 Other (e.g. meniscus, ear, ossicles) 3,815 3,883 Cartilage 3,423 3,588 Nr distributed (2022) Nr distributed (2021) General skeletal tissues 2021: EE, LT, NO, PT, and ES 2022: CY, EE, IT, LT, LU, NO, PT, and ES ©2023 EDQM, Council of Europe. All rights reserved. 16  2023 SARE Exercise (2022 data) Distributed Ocular Tissues by Type Distributed Cardiovascular Tissues by Type N= 40 327 N= 6 650 0 5,000 10,000 15,000 20,000 25,000 -300 200 700 1,200 1,700 2,200 2,700 3,200 3,700 4,200 4,700 18,790 4,432 Cornea Vessel 26,352 4,444 18,513 1,638 General ocular tissue Heart valve 2,553 1,508 Other CV tissue 2,753 417 Sclera (e.g. conduit, patch 1,953 362 or pericardium) 270 163 Other General CV 116 Nr distributed (2022) Nr distributed (2021) Nr distributed (2022) Nr distributed (2021) General ocular tissues General CV tissues 2021: AT, CZ, LV, LT, and NO 2021: LT and NO 2022: AT, CY, EE, FR, IT, NO, and ES 2022: DK and LU ©2023 EDQM, Council of Europe. All rights reserved. 17  2023 SARE Exercise (2022 data) Distributed Skin Distributed Other Replacement T&C by Type N= 14 531 N= 40 643 0 5,000 10,000 15,000 20,000 25,000 Skin units reported as cm2 are not included in the 22,776 total above Amniotic Membrane 16,908 Country Processed (cm²) Distributed (cm²) Belgium N/A 209,197 Other (e.g. adipose tissue, 16,078 France 600,000 420,000 tympanic membrane ) 4,157 Germany 113,174 202,646 Spain - 341,778 1,789 Pancreatic Islets 1,248 Nr distributed (2022) Nr distributed (2021) ©2023 EDQM, Council of Europe. All rights reserved. 18  2023 SARE Exercise (2022 data) Denominators: reporting countries Parameter General HPC Bone Marrow PBSC Cord Blood DLI Other 2 (4/2021) 18 (17/2021) 19 (15/2021) 5 (9/2021) 1113 (13/2021) 5 (5/2021) (HU and LT) (AT, BE, BG, DK, (AT, BE, BG, DK, (CY, IT, NL, PL, (AT, CZ, DK, EE, (AT, EL, HR, PL Distributed HR, CY, CZ, EE, HR, CY, CZ, EE, FI, and PT) EL, FI, HR, IE, IT, and SI) T&C FI, EL, IE, IT, NL, EL, IS, IE, IT, NL, NL, PL, RO, and PL, PT, SI, SE and NO, PL, PT, RO, SE) UK(NI)) and SE) 2 (3/2021) 18 (18/2021) 16 (15/2021) 6 (7/2021) 10 (12/2021) 4 (3/2021) (HU and LT) (AT, BG, CY, CZ, (AT, BG, DK, HR, (CY, FR, IT, NL, (AT, CZ, DK, FI,FR (AT, EL, HR and Recipients DK, EE, EL, FI, CY, CZ, FI, EL, FR, PT, and SE) HR, IE, IT, NL, and SI) FR, HR, IE, IT, IS, IE, IT, NL, NO, SE) NL, PL, PT, SI, SE PT, and SE) and UK(NI)) Note: Countries that reported “0” T&C are included. ©2023 EDQM, Council of Europe. All rights reserved. 19 Hematopoietic Stem Cells 2023 SARE Exercise (2022 data) Number of Distributed T&C by Sub-Category N= 46 291 Cord blood 15,494 34% Bone marrow 1,904 4% Donor lymphocyte infusions 1,330 3% Other HSC 675 1% General HSC 655 N= 38 597 1% Bone Marrow (auto+allo) Peripheral blood progenitor cells 1,846 (auto+allo) 26,233 Other Haematopoietic 5% Stem Cells (units) 559 Donor Lymphocyte Infusions 57% 1% 1,867 5% Cord Blood 2,604 7% General HPC Peripheral Blood Stem Cells (auto+allo) 4,347 27,374 11% The increase in the total number of HSC distributed in 2022 is due to the contribution of two 71% private cord blood banks (PT) that reported 15,160 units of autologous cord blood. ©2023 EDQM, Council of Europe. All rights reserved. 20 Hematopoietic Stem Cells 2023 SARE Exercise (2022 data) Distributed Peripheral Blood Stem Cells by Type N= 26 233 0 2,000 4,000 6,000 8,000 10,000 12,000 14,000 16,000 18,000 15,640 Autologous 12,194 5,493 Allogenic unrelated 2,789 2,751 General 10,721 2,349 Allogenic related 2021 1,670 Nr distributed (2022) Nr distributed (2021) ©2023 EDQM, Council of Europe. All rights reserved. 21 Hematopoietic Stem Cells 2023 SARE Exercise (2022 data) Distributed Bone Marrow by Type Distributed Cord Blood by Type N= 1 904 N= 15 494 0 200 400 600 800 1,000 1,200 1,400 0 2,000 4,000 6,000 8,000 10,000 12,000 14,000 16,000 651 15,280 General Autologous 1,206 1 629 210 Allogenic related Allogenic unrelated 380 75 577 3 Allogenic unrelated Allogenic related 226 5 47 1 Autologous General 35 2,523 Nr distributed (2022) Nr distributed (2021) Nr distributed (2022) Nr distributed (2021) ©2023 EDQM, Council of Europe. All rights reserved. 22 Hematopoietic Stem Cells 2023 SARE Exercise (2022 data) Distributed Donor Lymphocyte Infusions by Type Distributed Other HSC by Type N= 1 330 N= 675 0 100 200 300 400 500 600 700 0 200 400 600 800 1,000 1,200 563 624 General Autologous 1,089 494 Allogenic unrelated Allogenic unrelated 418 95 273 51 Allogenic related 360 General 464 Nr distributed (2022) Nr distributed (2021) Nr distributed (2022) Nr distributed (2021) ©2023 EDQM, Council of Europe. All rights reserved. 23  2023 SARE Exercise (2022 data) Denominators: reporting countries Other Reproductive Parameter Embryo (IVF) Sperm (IUI) T&C 19 (18/2021) 19 (18/2021) 13 (7/2021) (AT, BE, BG, CY, CZ, EE, (AT, BE, BG, DE, DK, FI, (AT, BE, CZ, DE, DK, EE, Distributed FI, HR, HU, IE, IS, LT, HU, HR, IE, IS, LT, LU, FI, HR, HU, LV, NL, SE, T&C LU, LV, MT, NL, RO, SE, LV, MT, NL, NO, RO, SE, and SI) and SI) and SI) 19 (14/2021) 18 (16/2021) 10 (6/2021) (AT, BG, CY, CZ, DK, EE, (AT, BG, CZ, DK, FI, HU, (AT, CZ, DK, HR, FI, LI, FI, HU, HR, IE, IS, LT, HR, IE, IS, LI, LT, LU, MT, NL, SE, and SI) Recipients LU, MT, NL, PT, SE, SI, NL, PT, SE, SI, and and UK(NI)) UK(NI)) Note: Countries that reported “0” T&C are included. ©2023 EDQM, Council of Europe. All rights reserved. 24 Denominators for Reproductive T&C 2023 SARE Exercise (2022 data) 1,800,000 1,779,943 1,787,524 300 1,600,000 253 250 1,400,000 211 1,200,000 200 181 172 1,000,000 966,690 148 835,060 131 150 150 786,451 124 761,919 800,000 738,282 670,565 596,244 600,000 100 81 494,304 506,429 477,684 79 400,000 245,849 255,748 228,771 50 223,647 216,157 187,511 162,868 200,000 142,197 156,651 114,568 100,598 110,816 15 29 0 0 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 Number Distributed Number Recipients Number SAR 2021: 13 countries reported SAR: BE, HR, CZ, DK, EE, FI, IE, IT, NO, PT, ES, SE, UK 2022: 14 countries reported SAR: BE, CZ, DE, DK, EE, FI, IT, LU, NL, NO, PL, PT, ES, SE ©2023 EDQM, Council of Europe. All rights reserved. 25 Reproductive T&C 2023 SARE Exercise (2022 data) Distributed T&C by Sub-category N= 506 429 Ovarian tissue 14,376 Testicular tissue 2,901 3% 0% Embryo 246,743 Sperm 49% 242,409 48% 2021 N= 761 919 Testicular tissue (2,465) Ovarian tissue (183) 0% 0% Sperm (234,661) 31% Embryo (524,610) 69% Comparable number of reporting countries (22/2023 vs 21/2021). The reduction in the total number of distributed reproductive T&C is explained by a significantly lower number of units of embryos reported (BE -210K units of embryos general, BG - 40K embryos and CZ -30K embryos). ©2023 EDQM, Council of Europe. All rights reserved. 26  2023 SARE Exercise (2022 data) Distributed Embryos by Type Distributed Sperm by Type N= 246 743 N= 242 409 0 40,000 80,000 120,000 160,000 200,000 Partner gametes 182,605 General 151,447 General 45,174 Partner donation 60,604 Donor sperm, partner oocyte 9,596 Non-partner donation 30,358 Donor oocyte, partner sperm 8,785 0 20,000 40,000 60,000 80,000 100,000 120,000 140,000 160,000 Donor sperm and oocyte 583 N= 524 610 Embryo donor oocyte, N= 234 661 Sperm non-partner donation partner sperm (24,710) Embryo donor sperm (30,401) 5% and oocyte (33,270) 13% 6% Embryo donor Sperm partner donation sperm, partner Sperm general (55,181) Embryo general oocyte (8,082) (149,079) 23% Embryo partner (275,496) 2% 64% gametes (183,052) 52% 35% ©2023 EDQM, Council of Europe. All rights reserved. 27  2023 SARE Exercise (2022 data) SAR in Recipients 17 Countries: BE, BG, CZ, DE, DK, EE, ES, FI, FR, EL, IT, LU, NL, NO, PL, PT, and SE ©2023 EDQM, Council of Europe. All rights reserved. 28 Total SAR 2023 SARE Exercise (2022 data) Total SAR in Recipients by Country in 2022 90 81 79 80 70 60 50 40 40 30 28 30 20 18 16 8 10 9 10 5 5 5 7 4 1 1 2021 0 70 64 60 53 53 50 40 31 30 23 24 14 17 20 5 5 6 7 7 4 5 10 3 1 2 2 2021: 326 SAR reported by 19 countries 0 2022: 339 reported by 17 countries (same as in 2021 -AU, -HR, -IE, -UK, +BG, +LU) ©2023 EDQM, Council of Europe. All rights reserved. 29 SAR by Country and Category of T&C 2023 SARE Exercise (2022 data) 0 10 20 30 40 50 60 70 80 Belgium (BE) 2 1 5 Bulgaria (BG) 5 Czechia (CZ) 81 Denmark (DK) 2 2 Estonia (EE) 1 Finland (FI) 5 France (FR) 1 29 Germany (DE) 15 7 6 Greece (EL) 3 7 Italy (IT) 2 2 1 Luxembourg (LU) 1 Netherlands (NL) 4 3 Norway (NO) 18 Poland (PL) 16 Portugal (PT) 2 38 Spain (ES) 9 2 68 Sweden (SE) 1 8 Replacement Tissues & Cells Haematopoietic Stem Cells Reproductive Tissues & Cells ©2023 EDQM, Council of Europe. All rights reserved. 30  2023 SARE Exercise (2022 data) SAR 2022 SAR 2021 Number of SAR by Sub-category of T&C 45 28 40 N= 34 35 15 30 25 20 16 15 12 11 Other tissues or cells 1 10 3 5 1 Cardiovascular tissues 5 3% 5 0 1 15% 0 SKELETAL OCULAR TISSUES CARDIOVASCULAR SKIN OTHER TISSUES TISSUES TISSUES OR CELLS Skeletal tissues 16 47% N = 58 Ocular tissues 12 Other tissues or cells (11) 35% 19% Skeletal tissues (15) Skin (1) 26% 2% Cardiovascular tissues (3) 5% Ocular Tissues (28) 48% 2021: 9 countries reported 58 SAR: AT, BE, DE, EL, FR, IE, NL, PL, ES 2022: 10 countries reported 34 SAR: BE, BG, DE, EL, FR, IT, NL, PT, ES, SE ©2023 EDQM, Council of Europe. All rights reserved. 31  2023 SARE Exercise (2022 data) Replacement Tissues T&C Sub-Type SAR SAR Could the dramatic reduction in & Cells 2022 2021 SAR related to cornea be due to the reduction in # of recipients Bone 11 10 of corneal transplant in 2022? Tendons/ligaments 1 2 Skeletal tissues Cartilage - 2 General skeletal tissues 3 1 Tissue Type # Distributed # Recipients # SAR Other (e.g., meniscus, ear, ossicles) 1 - 2022 2021 2022 2021 2022 2021 Cornea 2 28 Cornea 18791 26352 5659 15724 2 28 Ocular tissues General ocular tissue 7 - Other 3 - Sclera 2753 2553 1973 1121 - - Heart valve 5 1 Cardiovascular tissues 18513 1953 11334 1069 7 - Vessel - 2 General ocular tissues Skin Skin - 1 Other ocular 270 - 214 2 3 - Amniotic membrane - 11 tissues Other tissues or cells Other (adipose, tympanic membrane) 1 - Total SAR 34 58 10-fold increase in the number of recipients of general ocular tissues in 2022 ©2023 EDQM, Council of Europe. All rights reserved. 32  Replacement T&C 2023 SARE Exercise (2022 data) Distribution of SAR by Type of Reaction N = 34 Transmitted infections 0 5 10 15 20 Bacterial (3) 1 1 1 2021 N = 58 Reaction Category Skeletal Ocular CV Other tissues tissues tissues Skin T/C Fungal (3) 3 Bacterial inf. (5) 4 1 Viral other (2) 2 Fungal inf. (4) 4 Graft failure/ Immunological 13 7 3 reactions (3) 3 delayed (23) Other SAR Graft failure/ delayed (28) 14 12 1 1 Undue exposure to Undue exposure to 3 risk interventions (3) 1 1 1 risk interventions (3) Other (13) 2 11 Other (2) 1 1 Skeletal tissues Ocular Tissues Cardiovascular Tissues Other tissues or cells ©2023 EDQM, Council of Europe. All rights reserved. 33 Replacement T&C 2023 SARE Exercise (2022 data) SAR Type 1 Transmitted Infections (6) Type of Tissue Type / # SAR IL Pathogen Description infection Subtype Bacterial Cardiovascular tissue 1 - Staphylococcus Heart valve contaminated by Staphylococcus epidermidis (heart valve) epidermidis General Ocular 1 3 Corynebacterium Ocular infection by Corynebacterium Striatum. It was detected in CC-3 but without culture in the patient. There were infection signs. Tissues striatum Ocular tissues 1 3 Proteus mirabilis January 21st, 2022, transplant centre – microbiological testing of a tissue sample; result: contamination with Proteus mirabilis; treatment with Cefuroxime 500 mg / 12 h at home; (decellularized intraarticular joint puncture positive for Proteus mirabilis (Feb 07); tissue explant is dermal matrix) performed on 16/2/2022 (infection signs); tissue culture on sample taken at explantation is positive for Proteus mirabilis. Patient is hospitalized 1 week and treated with iv antibiotic, followed by a 3-week treatment with antibiotic at home. The patient recovered from the infection; no subsequent surgical intervention. Imputability investigation: 2 decellularized dermal matrix out of 3 from the same donor (still in stock, not transplanted) were contaminated with Proteus mirabilis. Process improvement: New microbiological test (tissue sample in thioglycolate and solution in BacTec™) of the preservation media one week after packaging. Fungal Ocular tissues 2 3 - Contamination of storage media leading to infection in cornea (cornea) General Ocular 1 2 Candida albicans Endophthalmitis caused by C. Albicans with positive pre-implant culture Tissues ©2023 EDQM, Council of Europe. All rights reserved. 34  Replacement T&C 2023 SARE Exercise (2022 data) SAR Type 4 Other SAR (28) Graft failure / delayed engraftment (23) Tissue # SAR IL Description Type/Subtype Cardiovascular 3 1 • Graft degeneration Tissues • Stenosis • Aortic valve insufficiency due to aortic valve degeneration Ocular issues 1 1 Complete endothelial graft detachment (Cornea - Sclera - 3 Graft failure Other Ocular 2 1 • Asymmetric lamella and evolution to oedema with reimplantation. It is an AE that progressed to AR. Tissues) • Patient with previous DSAEK implant failure, who required reimplantation by the same technique. The injury required another Undue technique (keratoplasty). exposure to 1 2 Graft rejection due to low cellularity and long conservation time risk intervention Skeletal Tissues 11 1 Bone block non-integration, inflammation ? 1 3 Left medial meniscus obtained by the tissue bank's examination team. The tissue bank 's team was still in training and under supervision. It is difficult to determine whether the tissue bank's employee responsible for the documents and the labelling of the jars has pasted an incorrect label, or whether an intern/someone of the tissue bank employees / professional named the graft incorrectly. In the meantime, the tissue bank prelevators have been declared competent to independently pre-deliver and have been well trained, which means that the prelevations are now much smoother. On inquiry it appears that the patient was already under anaesthesia, and that the incision had already been made. Graft was not transplanted but destroyed in the hospital. 1 3 A left extensor delivered on 29/07/2017; expiry date: May 2022. Tissue Establishment + Surgeon were aware of this. The graft was packed in 1 EVA bag and 2 regular kidney bags, which were only tied closed. The last bag was left unfolded and glued shut. Presumably this was still allowed in 2017. However, in the meantime the packaging rules have become stricter and there is also stricter supervision to ensure that this is carried out correctly. Large bone pieces and autologous skull hatches are still packed in 3 sterile bags, but the bow tie is now folded inwards, and it is again glued with a sterile tape. However, the patient was already under anaesthesia and the incision was already made when it was determined that the graft had not been packaged in accordance. There is narcosis of the patient and incision for no reason since the material could not be grafted because of the suspicion of non-sterility. ©2023 EDQM, Council of Europe. All rights reserved. 35  Replacement T&C 2023 SARE Exercise (2022 data) SAR Type 4 Other SAR (28) Undue exposure to risk-intervention (3) Tissue # SAR IL Description Type/Subtype Skeletal Tissues 3 3 • Tendon considered low quality discarded during surgery; autologous tendon used instead. • Delayed shipment and patient under anaesthesia for hours. • Patient under anaesthesia, but the tissue delivered tissues was not the requested one. SAR Type 4 Other SAR (28) Reactions other than those listed above (2) Tissue # SAR IL Description Type/Subtype Cardiovascular 1 1 • Acute aortic insufficiency due to endocarditis (fatal) Tissues Ocular Tissues 1 - • Tissue contamination prompting a second transplant of cornea (Cornea) ©2023 EDQM, Council of Europe. All rights reserved. 36 Hematopoietic Stem Cells 2023 SARE Exercise (2022 data) Number of SAR by Sub-category of T&C 70 61 60 N = 60 50 40 44 30 19 20 General HSC 2 10 3 4 1 3% 11 0 2 Bone marrow 11 Peripheral blood Cord blood Bone marrow 2 General HSC Other HSC 19% Other HSC 1 progenitor cells 2% (auto+allo) SAR 2022 SAR 2021 Cord blood 2 3% 2021 N = 87 Peripheral blood General HPC (4) 5% progenitor cells Cord blood (3) 3% (auto+allo) 44 Bone marrow 73% (auto+allo) (19) 22% Peripheral blood 2021: 10 countries reported 87 SAR: BE, DE, DK, EL, FR, IE, IT, NL, PT, ES progenitor cells (auto+allo) (61) 2022: 7 countries reported 60 SAR: BG, DE, DK, EL, FR, IT, ES 70% ©2023 EDQM, Council of Europe. All rights reserved. 37  2023 SARE Exercise (2022 data) 0 Distribution 2 of SAR 4 by Type 6 of Reaction 8 N =10 60 12 14 16 Bacterial infection (2) 2 Transmitted infections Viral: other (1) 1 Cardiovascular reactions (1) 1 Pulmonary reactions (3) 2 1 Renal complications (4) 4 Neurological reactions (2) 1 1 Other SAR Toxicity (6) 1 4 1 Immunological reactions (15) 1 14 Graft failure/delayed (7) 4 3 Undue exposure to 1 risk interventions (1) Infusion related 4 non specific symptoms (4) Other (14) 1 1 10 1 1 General HPC Bone marrow Peripheral blood progenitor cells Cord blood Other HPC ©2023 EDQM, Council of Europe. All rights reserved. 38  2023 SARE Exercise (2022 data) HSC Category HSC Type SAR SAR 2022 2021 Allogenic related 4 8 Bone marrow Allogenic unrelated 6 5 General 1 6 Allogenic related - 3 Cord blood Allogenic unrelated 2 - Allogenic related 9 10 Peripheral blood Allogenic unrelated 19 31 progenitor cells Autologous 10 7 General 6 13 General HPC - 2 4 Other HPC Autologous 1 - Total SAR 60 87 ©2023 EDQM, Council of Europe. All rights reserved. 39  2023 SARE Exercise (2022 data) Type of SAR Sub-type of SAR HSC Type HSC Sub-type N = 60 Allogenic Allogenic Autologous General Related Unrelated Transmitted infections (3) Bacterial infection (2) Bone marrow (2) 2 Viral: other (1) PBSC (1) 1 Other SAR (57) Graft failure/delayed Bone marrow (4) 1 3 3 engraftment (7) PBSC (3) 1 1 1 Immunological reactions Bone marrow (1) 1 (15) PBSC (14) 4 4 4 2 Infusion related non-specific PBSC (3) 3 symptoms (3) Renal complications (4) PBSC (4) 1 3 Pulmonary reactions (3) Bome marrow (2) 1 1 PBSC (1) 1 Neurological reactions (2) General HSC (1) PBSC (1) 1 Cardiovascular reaction (1) PBSC (1) 1 Toxicity (6) General HSC (1) Cord blood (1) 1 PBSC (4) 1 1 2 Undue exposure to PBSC (1) 1 risk interventions (1) Others (15) Bone marrow (1) 1 Cord blood (1) 1 General HSC (1) PBSC (11) 1 5 3 2 Other HSC (1) 1 ©2023 EDQM, Council of Europe. All rights reserved. 40  2023 SARE Exercise (2022 data) SAR Type 1 Transmitted infections (3) Type of Tissue # SAR IL Description Infection Type/Subtype Bacterial Bone marrow 1 2 • A 7-year-old girl was subjected to a transplant of bone marrow from her mother (allogenic donation. A control performed on a bone marrow sample returned positive to related) Staphylococcus saccharolyticus. A treatment was initiated at D4 post graft on a diagnosis of febrile aplasia. The initial treatment included Vancomycin and Tazocilline, then Tazocilline was stopped 3 days later. At D11, fever occurred (40°C); Tazocilline was reintroduced and changed to Meropenem 72h later. Patient outcome (at the time of the notification closure): at 2 months post graft, the number of neutrophils was restored and at 3 month following the graft; number of transfusions of platelets reduced. 1 2 • A 4-month year old boy was subjected to a transplant of bone marrow from his father donation. A control performed on a bone marrow sample returned positive to Cutibacterium acnes. The recipient developed an atypical cutaneous rash (face and torso) probably linked to this contamination. A treatment with antibiotic was initiated. Aplasia considered corrected 3 weeks later. Viral: other PBSC (allogenic 1 - • Other related) SAR Type 2 Malignant diseases + SAR Type 3 Other disease transmission: None reported in 2022 ©2023 EDQM, Council of Europe. All rights reserved. 41  2023 SARE Exercise (2022 data) SAR Type 4 Other SAR (57) Immunological reactions (15) Toxicity (6) Reactions other (15) • Graft versus host disease • Reaction to DMSO (malaise, nausea, • Macrophage activation syndrome • Haemolytic reaction due to the stem vomiting, fall in blood pressure, • Veno-occlusive disease cells 11 days after transplantation, tachycardia, hoarseness, abdominal • Septicaemia explained by the production of donor cramps, oedema of face and lips) • Epstein-Barr virus associated plasma cells (which produce anti-A • Reaction to DMSO (headache, nausea, lymphoproliferative disorder antibodies) and not by the incompletely back pain, vertigo, arterial removed plasma in the stem cell hypotension) • Epstein-Barr virus associated lymphoma products, the so-called “passenger • Reaction to DMSO (vasodilatation, • Human herpesvirus 6 infection; leucocyte syndrome”. malaise, nausea, RR-decrease, neutropenic colitis; death 3 days post- • Passenger lymphocyte syndrome sweating) transplant • Mucor mycosis infection, acute graft • Anaphylactic shock and suspected brief • Haemolytic transfusion reaction versus host disease, autoimmune cardiac arrest; patient stabilized (ICU); • Temperature increase, chills, blood thrombocytopenia; death 2 months remaining cells washed and infused pressure increase, tachycardia post-transplant with moderate adverse reaction. • Uncommon effects tied to the donation • Allergic or pseudo allergic reaction Patient outcome: no lasting effects or process consequences. • Label of internal bag damaged; the • Urticaria • Malignant hypertension patient had to undergo a second • Dyspnoea and erythema apheresis (autologous transplant) ©2023 EDQM, Council of Europe. All rights reserved. 42  2023 SARE Exercise (2022 data) SAR Type 4 Other SAR cont. Graft failure / delayed engraftment (7) Cardiovascular reactions (1) Neurological reactions (2) • Post-infusion stroke Pulmonary reactions (3) • Circulatory overload • Refractory thrombotic microangiopathy Renal complications (4) • Haemolytic uremic syndrome Undue exposure to risk interventions • Patient conditioning interrupted due to donor (1) unavailability for PB and BM donation • Hyperthermia Immunological Infusion related non-specific symptoms reaction? (3) • Graft versus host disease ©2023 EDQM, Council of Europe. All rights reserved. 43  2023 SARE Exercise (2022 data) 250 N= 253 200 195 150 119 100 62 Other Reproductive 50 Tissues 16 42 16 6% 0 0 Embryo Sperm Other Reproductive Tissues SAR 2022 SAR 2021 Sperm 42 17% N = 181 Embryo 195 Ovarian tissue (0) 77% 0% Sperm (62) 34% Embryo (119) 66% ©2023 EDQM, Council of Europe. All rights reserved. 44  2023 SARE Exercise (2022 data) 30% increase in the number of cases of transmitted genetic Reproductive SAR SAR conditions and 100% increase in Tissues & Cells T&C Sub-Type 2022 2021 the number of ectopic pregnancies comparing to 2021 EMBRYO Donor oocyte, partner sperm 83 50 Donor sperm and oocyte 21 15 Donor sperm, partner oocyte 19 17 Partner gametes 55 29 General 17 8 SPERM Non-partner donation 31 56 6 Partner donation 7 Other Reproductive Other 16 - T&C Total 195 181 ©2023 EDQM, Council of Europe. All rights reserved. 45  2023 SARE Exercise (2022 data) SAR Types in Embryos N = 195 0 20 40 60 80 100 120 Transmitted infection 4 (bacterial) (4) Transmitted Genetic 63 16 15 13 1 Conditions (108) Ectopic pregnancy (62) 17 4 3 35 3 Molar pregnancy (3) 1 2 Other SAR (18) 3 1 7 7 Donor oocyte, partner sperm Donor sperm and oocyte Donor sperm, partner oocyte Partner gametes General 2021 Transmitted Ectopic Molar Pregnancy Bacterial Embryo Genetic pregnancy pregnancy of unknown infection Pneumonia Conditions (83) (30) (1) origin (1) ovaries (3) (1) Donor oocyte, partner sperm 46 3 1 Donor sperm and oocyte 14 1 Donor sperm, partner oocyte 14 3 Partner gametes 5 23 1 Embryo General 4 3 1 ©2023 EDQM, Council of Europe. All rights reserved. 46  2023 SARE Exercise (2022 data) SAR Types in Sperm N = 42 -1 1 3 5 7 9 11 13 15 17 Transmitted Infections (1) 1 Other disease transmissions 15 (transmitted genetic disease) (15) Ectopic pregnancy (requiring surgical 4 6 intervention or hospitalization) (10) Other SAR (16) 11 1 4 Non-partner donation Partner donation General 0 5 10 15 20 2021 Transmitted Genetic Conditions (24) 24 Ectopic pregnancy (7) 1 6 Other disease transmission (13) 13 Anaphylactic reaction (7) 7 Other SAR (11) 11 Sperm Non-partner donation (56) Sperm Partner donation (6) ©2023 EDQM, Council of Europe. All rights reserved. 47  2023 SARE Exercise (2022 data) SAR Type 1. Transmitted infections (5) SAR Type 4. Other SAR (125) • Other transmitted infections – Infection • Ectopic pregnancy (72) (Sperm (IUI) • Molar pregnancy (3) • Other reactions (50): • Bacterial infection after embryo transfer • OHSS (20) (4 cases) Embryo (IVF) • Death after delivery (without recognized genetic condition) • Mix-up of embryo during transfer • Cervical stenosis: embryo transfer not possible, with loss of the embryo during procedure • Pelvic inflammatory disease SAR Type 3 • Epilepsy • Newborn with cleft palate • Ovarian torsion after embryo transfer, that required surgical detorquation/ removal of ovary • Abort • Transmitted genetic conditions (1x Autosomal recessive hereditary disease: SPATA-5 ?? associated developmental delay, 2x CFTR mutation/cystic fibrosis, 1x clinical diagnosis of Pierre Robin sequence • Donor selection ©2023 EDQM, Council of Europe. All rights reserved. 48  2023 SARE Exercise (2022 data) SAR Type 3. Transmitted genetic conditions (108) SAR Type 3. Other disease transmission (15) • Child with HPA (hyperphenylalaninemia); pathogenic mutation confirmed in both offspring and donor • Newborn with hearing loss --> homozygous • Termination of pregnancy due to serious heart defects and genitourinary abnormality pathogenic mutation (c.35delG) in the GJB2 gene (Connexin 26) located on chromosome 13q11. in foetus, determined at 23 weeks of pregnancy; pregnancy after the transfer of a cryo-embryo (IVF/ICSI with donor semen. Donor carrier of polycystic kidney disease. • Newborn with VLCADD (autosomal • Termination of pregnancy with donor oocyte due to congenital anomalies (Pentalogy of recessive). Cantrell) • Newborn with suspected genetic disease; • Newborn with CNF (homozygous); donor carrier of the mutation donor carrier of a variant in USH2A (c.1606T>C p.(Cys536Arg)). • Congenital deafness (8-year-old boy); molecular analysis confirms the presence of the same mutation in the oocyte donor and in the boy; donor blocked • GRN-related frontotemporal lobar • Child born with rhabdomyomas. Although there is not enough consistency for its degeneration due to mix of PGT embryos genetic diagnosis, the donors are blocked • Agenesis of the corpus callosum, • Voluntary termination of pregnancy at week 12 due to a poly malformed foetus. potentially due to genetic inheritance Donors are blocked. • Cartilage-hair hypoplasia, both donor and • Twin birth in which one of the children is diagnosed at age 7 with type II autism recipient are carries of recessive autosomal gene mutation • Boy diagnosed at 4 years of age with autism spectrum disorder, carrier of a deletion in Chromosome 15. A genetic study of the semen donor confirmed the donor as a carrier • Bilateral lip cleft - multifactorial inheritance of said deletion • Neurological disease - autosomal recessive • Child born with autism spectrum disorder. Despite the fact that the genetic study of the POLG1 mutation child is normal, the donor is excluded. • Child carrier of variant in the SCN5A gene • Autism associated with severe alteration of the heart rhythm. Both the child and the sperm • Abort (29) donor carry the same variant (7 cases) • Children (born) (37) ©2023 EDQM, Council of Europe. All rights reserved. 49  2023 SARE Exercise (2022 data) Imputability Reporting (2022 vs 2021) Total number SAR with Imputability Level of SAR imputability 2022 2021 T&C Category reported 2022 2021 2022 2021 IL1 IL2 IL3 IL1 IL2 IL3 Replacement 29 41 34 58 18 2 9 27 7 7 T&C (85%) (71%) 45 65 HSC 60 87 23 16 6 41 14 10 (75%) (75%) Reproductive 59 9 253 181 29 10 20 7 - 2 T&C (23%) (5%) 133 115 Total 347 326 70 29 34 75 21 19 (38%) (35%) ©2023 EDQM, Council of Europe. All rights reserved. 50  2023 SARE Exercise (2022 data) Serious Adverse Events 22 Countries: AT, BE, BG, DE, DK, EE, EL, ES, FI, FR, HU, IE, IS, IT, MT, NL, NO, PL, PT, RO, SE, and SI (No SAE from HR, CY, LI, LT, LU, LV, RO, and UK(NI)) ©2023 EDQM, Council of Europe. All rights reserved. 51 SAE Denominators 2023 SARE Exercise (2022 data) 3500000 1200 694 1133 3,159,362 949 3000000 2,922,117 2,892,459 1000 739 910 2,584,557 622 2,443,564 2500000 2,280,512 769 756 800 2000000 1,862,293 1,775,082 441 551 600 1,550,701 499 1,433,828 1500000 426 400 1000000 887,536 748,753 200 500000 0 0 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 Tissues Processed Number SAE ©2023 EDQM, Council of Europe. All rights reserved. 52 T&C Processed 2023 SARE Exercise (2022 data) Exercise 2023 Total Number of T&C Processed by Country Replacement HSC T&C Reproductive Exercise Country T&C Processed Processed T&C Processed 2023 Exercise 2022 Exercise 2021 Exercise 2020 2021-2020 2022-2021 2023-2022 Austria (AT) 89,291 2,272 153,443 245,006 208,704 196,948 208,545 -11,597 11,756 36,302 Belgium (BE) 487,986 0 0 0 487,986 -487,986 Bulgaria (BG) 801 1,149 27,223 29,173 129,711 118,546 126,876 -8,330 11,165 -100,538 Croatia (HR) 729 1,691 45,942 48,362 54,154 50,690 62,585 -11,895 3,464 -5,792 Cyprus (CY) 2,637 1,918 1,988 6,543 6,543 Czechia (CZ) 13,338 3,288 447,027 463,653 390,898 397,423 422,543 -25,120 -6,525 72,755 Denmark (DK) 1,939 883 148,482 151,304 51,975 45,174 132,763 -87,589 6,801 99,329 Estonia (EE) 910 311 1,221 1,163 34,838 40,766 -5,928 -33,675 58 Finland (FI) 3,150 771 43,934 47,855 3,863 4,515 6,119 -1,604 -652 43,992 France (FR) 56,273 56,273 0 0 0 0 0 56,273 Germany (DE) 176,334 855,129 1,031,463 1,029,866 1,002,175 856,324 145,851 27,691 1,597 Greece (EL) 4 10 14 1 28 45 -17 -27 13 Hungary (HU) 529 8,854 21,415 30,798 27,273 39,359 43,524 -4,165 -12,086 3,525 Iceland (IS) 77 915 992 992 Ireland (IE) 726 854 82,035 83,615 103,835 71,763 83,451 -11,688 32,072 -20,220 Italy (IT) 10,903 5,905 16,808 15,019 15,876 44,093 -28,217 -857 1,789 Latvia (LV) 96 33 39,803 39,932 31,912 29,514 40,089 -10,575 2,398 8,020 Liechtenstein (LI) 283 283 197 0 0 0 197 86 Lithuania (LT) 2,795 19,165 -16,370 -2,795 0 Luxembourg (LU) 7410 7,410 6,411 1,770 2,112 -342 4,641 999 Malta (MT) 6 3,586 3,592 801 1,820 807 1,013 -1,019 2,791 Netherlands (NL) 12,874 2,417 246,932 262,223 261,382 222,020 248,064 -26,044 39,362 841 Norway (NO) 0 0 66,072 -66,072 0 0 Poland (PL) 49,530 30,764 80,294 77,407 78,645 55,585 23,060 -1,238 2,887 Portugal (PT) 1,283 11,241 12,524 11,397 92,818 113,424 -20,606 -81,421 1,127 Romania (RO) 261 261 4,785 1,893 1,551 342 2,892 -4,524 Slovakia (SK) 20,920 -20,920 0 0 Slovenia (SI) 427 1,713 34,904 37,044 35,934 27,627 40,190 -12,563 8,307 1,110 Spain (ES) 30,567 30,567 29,251 26,888 36,552 -9,664 2,363 1,316 Sweden (SE) 4,345 1,920 198,819 205,084 195,306 77,083 180,557 -103,474 118,223 9,778 UK (NI) 165 165 131 105,871 69,395 36,476 -105,740 34 Total 456,953 76,236 2,359,270 2,892,459 3,159,362 2,646,079 2,922,117 -276,038 513,283 -266,903 ©2023 EDQM, Council of Europe. All rights reserved. 53 SAE and SAR by Country (2022) 2023 SARE Exercise (2022 data) 476 450 400 350 300 282 250 200 150 100 81 79 64 66 55 42 40 50 30 28 22 24 17 18 7 8 3 5 11 14 4 1 1 9 5 14 10 1 5 1 1 7 5 8 16 2 9 9 0 Total SAE Total SAR ©2023 EDQM, Council of Europe. All rights reserved. 54 Total SAE 2023 SARE Exercise (2022 data) Distribution of SAE by Specification and by Year (2010 - 2022) 1000 399 217 800 213 Other 168 126 156 70 149 Human error 600 109 295 190 119 System failure 128 Materials 295 357 248 122 148 145 311 Equipment failure 400 87 119 53 331 189 47 41 Tissue/cell defect 26 48 263 55 43 148 175 78 39 168 49 193 67 200 37 8 91 65 60 290 276 94 81 228 234 254 82 188 149 117 121 100 82 79 47 0 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 ©2023 EDQM, Council of Europe. All rights reserved. 55  2023 SARE Exercise (2022 data) Distribution of SAE by Specification 2022 vs 2021 0 50 100 150 200 250 300 350 400 450 188 Tissue/cell defect 276 37 Equipment failure 43 49 Materials 41 274 SAE System failure 145 311 Cord blood 149 Human error 119 399 Other 70 2022 2021 ©2023 EDQM, Council of Europe. All rights reserved. 56 Replacement T&C 2023 SARE Exercise (2022 data) Distribution of SAE by Specification (2022) Distribution of SAE by Specification (2022 vs 2021) N=209 209 vs 170 90 80 84 70 60 52 52 46 50 34 40 30 33 18 23 26 20 7 10 0 2 2 System Other Tissue or Human Equipment Materials failure cell defect error failure Replacement T&C (2022) Replacement T&C (2021) Year Parameter System Other T&C Human Equipm Materials failure defect error ent failure 2022 T&C Processed 456,953 # Recipients 149,823 #/% SAE (209) 52 52 46 34 18 7 (3%) (25%) (25%) (22%) (16%) (9%) 2021 T&C Processed 373,486 # Recipients 132,176 #/% SAE (170) 33 23 84 26 2 2 (1%) (19%) (14%) (50%) (15%) (1%) ©2023 EDQM, Council of Europe. All rights reserved. 57 Replacement T&C 2023 SARE Exercise (2022 data) Distribution of SAE by Activity Step (2022) N=209 Distribution of SAE by Activity Step (2022 vs 2021) 209 vs 170 70 63 60 62 50 40 40 36 30 22 20 28 14 11 10 19 6 10 15 4 3 12 0 5 8 6 8 7 Replacement T&C (2022) Replacement T&C (2021) ©2023 EDQM, Council of Europe. All rights reserved. 58 Replacement T&C 2023 SARE Exercise (2022 data) Distribution of SAE by Activity Step and SAE Type N=209 0 10 20 30 40 50 60 Transport (11) 2 9 Donor selection (22) 10 4 8 Procurement (14) 1 6 7 Testing (40) 3 4 33 Processing (63) 24 10 3 6 8 12 Storage (10) 3 6 1 Product selection (6) 3 3 Issue (4) 4 Distribution (3) 2 1 Other (36) 6 2 2 16 3 7 Tissue or cell defect Equipment failure Materials System failure Human error Other • Ocular Tissues (Cornea) – Testing – Other (30): Positive microbiology results found after transplant (PT) • Ocular Tissues (Cornea) – Processing – Other (8): Unforeseen events during tissue preparation (PT) • Ocular Tissues (Cornea) – Processing – T/C Defect (19): Anatomical change of tissue pending implantation (PT) • CV Tissues (Other) – Processing – Equipment failure (8): Failure of freezing equipment (HU) • General ocular tissue and multiple T&C – Other – System failure (11): positive cultures of corneas in various steps post implant (ES) ©2023 EDQM, Council of Europe. All rights reserved. 59 Replacement T&C 2023 SARE Exercise (2022 data) Distribution of SAE by Specification • Absence of storage container • Bacterial contamination of graft • 25% (50 out • Bone sent when tendon was requested • Contamination of tissue during thawing in surgical room of 209) SAE • Cooler containing a skull flap that remained in the operating room were reported • Delayed delivery (4 hours) of heart valve with no negative impact on graft, patient or scheduled transplant apart from the under the SAE delayed intervention Specification • Detection of Enterococcus faecium due to inadequate Bioburden threshold. Recall and destruction of three batches. Adaptation of Bioburden threshold (in total 217 T&C affected) System failure • Expired graft (heart valve) delivered and transplanted. Failure to verify expiry date (twice). No inadvertent consequence on receiving patient. • Failure to deliver all tissues ordered by a tissue bank (one graft could not be located in the freezer) revealed issues with the inventory process. • Frozen corneal preservation fluid: The right cornea was successful used. Upon opening the recipient containing the left cornea, ice pellets were observed that the preservation liquid and cornea was very rigid. The cornea was discarded. Investigation results: the preservation fluid Eusol was within expiry date, none of the other containers stored in the same refrigerator were affected, the temp. in the refrigerator was adequate; simulation of transport condition (on a box with • Sufficient carbonic snow) on discarded tissue and storage of packaged corneas close to the wall of the fridge could not reproduce the information incident. The cause remained unknown. not always • Coagulase negative S.A culture on implant: Implanting centre notified detection of methicillin-resistant S. Aureus in the sample taken during cancellous bone chip implantation. The patient didn´t display infection signs. Immediate measures: provided quarantine of tissues until conclusion of investigation. Review of donor history and controls post donation. No positive cultures. Review of all implants performed from the same donor confirmed absence of positive cultures or other issues. The microbiologist hypothesized that contamination could have occurred during sample handling at surgery time. ©2023 EDQM, Council of Europe. All rights reserved. 60 Replacement T&C 2023 SARE Exercise (2022 data) Distribution of SAE by Specification - cont. • Identification errors of tissue (heart valve) discovered during interbank transfer. • Corneas implanted with subsequent receipt of various positive cultures in different phases of the process • 25% (50 out • Inadequate transport conditions of heart from procurement centre to the TE of 209) SAE • Incomplete registry were reported • Loss of graft under the SAE • Mix-up of serological tests during transport, procured tissues lost • Non-compliance with the procurement procedure (cut in the commissure of the pulmonary valve during heart Specification removal; incision of the pulmonary and aortic valves). Loss of tissue System failure • Non-conforming tissue (heart valve) shipped inadvertently (positive bacteriological result not in the system). Tissue returned due to not being used; tissue rejected. • Positive test in smear of pulmonary heart valve during implantation: Cutibacterium acnes (1 T&C affected) • Positive test in smear of pulmonary heart valve during implantation: Staphylococcus lugdunensis (1 T&C affected) • Post donation information • Sufficient • Recipient ocular infection prior to transplant information • Retrieval of tissues (ocular tissues) without prior consent on the basis that, by law, anyone is a donor unless not always declared against during lifetime. provided • Temperature probe for traceability not present in the transport boxes • Transport box of the graft brought by the carrier not adapted • Traceability loss due to failure of repositories to provide tissue bank with documentation. • Traceability to transplanted bone lost as the user report was missing. Omission to follow the correct procedure was attributed to a lack of habit/training ©2023 EDQM, Council of Europe. All rights reserved. 61 Replacement T&C 2023 SARE Exercise (2022 data) Distribution of SAE by Specification • Different serological test detection threshold at tissue bank and receiving blood • 25% (50 out of 209) SAE vessel bank. Patient dies days later. Remaining tissue is rejected. Tissue bank were reported under the releases femoral veins to blood vessel bank. One vein had been transplanted when SAE Specification Other the tissue bank notifies the blood vessel bank about a slight positive NAT result for HCV. NAT test performed by receiving bank, but the result is negative. The difference is due to different serological test detection threshold at the two banks. • Contamination • Growth (Cutibacterium acnes - skin commensal) from anaerobic culture bottle post • SAE Specification cornea transplantation. No patient reactions/issues was notified by clinician. potentially inaccurate. • Positive microbiology results found after transplant (11) • Potentially not reportable • Positive microbiology results found before transplant (19) as SAE • Post donation information • Preparation error • Insufficient information • Storage time expired provided • Unforseen events during tissue preparation (8) ©2023 EDQM, Council of Europe. All rights reserved. 62 Replacement T&C 2023 SARE Exercise (2022 data) Distribution of SAE by Specification • Donor was accepted even though S-TrpaAb result was missing • 6% ( 13 out of 209) SAE • Sampling procedures not respected were reported under the • Bacterial contamination of the graft SAE Specification Human • Finding of the absence of corneal graft when opening the vial Error - Other, or no • Discovery of a hair while preparing the graft information to assign • Positive microbiological test result after cornea was distributed, most probably secondary contamination (1 T&C affected, respectively) • Contamination • A different SAE • Loss of 2 bulbi, box dropped Specification could be • When the graft (femoral head) was removed, standard serological and assigned to each. bacteriological tests were taken, however the material has not been delivered to the laboratory by the transport service. As it was no possible to retake the material for testing, the graft has been destroyed. ©2023 EDQM, Council of Europe. All rights reserved. 63  2023 SARE Exercise (2022 data) Distribution of SAE by Activity Step N=689 Distribution of SAE by Activity Step 689 vs 291 250 225 200 160 139 150 108 100 100 106 50 26 13 9 6 19 2 1 15 12 15 7 8 0 5 4 HSC (2022) HSC (2021) ©2023 EDQM, Council of Europe. All rights reserved. 64  2023 SARE Exercise (2022 data) Distribution of SAE by Specification N=689 Distribution of SAE by Specification (2022 vs 2021) 689 vs 291 350 333 300 250 205 200 162 150 99 100 50 23 18 11 33 39 0 24 19 14 Other System Tissue or Materials Human Equipment failure cell defect error failure HSC (2022) HSC (2021) ©2023 EDQM, Council of Europe. All rights reserved. 65  2023 SARE Exercise (2022 data) Distribution of SAE by Activity Step and SAE Type N=689 0 50 100 150 200 Transport (9) 211 5 Donor selection (108) 8 95 23 Procurement (139) 37 4 82 3 13 Testing (160) 31 7 1 148 Processing (225) 40 2 9 18 9 147 Storage (13) 1 7 5 Product selection (6) 5 1 Issue (1) 1 Distribution (2) 11 Other (26) 3 1 4 11 16 Tissue or cell defect Equipment failure Materials System failure Human error Other • Cord blood - Donor selection – System failure (94): Incomplete registry (PT) • Bone Marrow – Procurement – System failure (42): Bacterial contamination of graft (FR) • Cord blood - Testing – Other (131): Positive microbiological results before transplant (PT) • Cord Blood - Processing – Other (143): Low cell count (PT) ©2023 EDQM, Council of Europe. All rights reserved. 66  2023 SARE Exercise (2022 data) Distribution of SAE by Specification • Anaerobic culture positive for Cutibacterium acnes. Result available after infusion of allogenic PBSC. All other results negative, including sterility test for the 2nd unit collected at the same time. • Anomaly during the identification process • 30% (205 out of • Bacterial contamination of the graft (65) • Bacteriological test result indicates contamination of cells (PBSC) with Staphylococcus capitis. Prophylactic 689) SAE were antibiotics; additional blood cultures from used units tested negative reported under the • Blood culture incubation time too short (1 T&C affected) SAE Specification • Cancellation of ongoing DLI thaw, loss of mononuclear cells System failure • Culture flasks for testing discarded accidentally (1 T&C affected) • Detection of Cutibacterium acnes, E coli, Staph. Sp, Bacillus cereus, aerobic spore formers (22) • European sourced cells (lymphocyte infusions) received with delay and incomplete documentation (serology testing results not provided). • Incomplete and inaccurate documentation provided along with cellular product. • Sufficient • Incomplete registry (95) information not • Insufficient cell quantity, venous access problem always provided • Mislabelling with incorrect warning information (1 T&C affected) • Omission to perform microbiological testing in anaerobic conditions discovered after bone marrow infusion. No consequence for the allograft recipient. Other results negative. Physician notified. Patient under observation. • Organisational failure of the graft, lack of coordination between the various teams involved in the care of a patient, destruction of a labile blood product • Poor recovery of the CD34+ cells after deserythrocytosis • Poor recovery of cryopreserved lymphocyte after thawing • Suspected mix-up of cryopreserved stem cells (3 T&C affected) ©2023 EDQM, Council of Europe. All rights reserved. 67  2023 SARE Exercise (2022 data) Distribution of SAE by Specification • Bacterial contamination • Bacterial contamination. Product infused. • Bacterial contamination. Required extra days harvest. Implicated product was not used. • Contamination • Cryobag with stem cell burst • 48% (333 out of 689) • Delayed delivery of samples for testing (1 T&C affected) SAE were reported • Donor with donation contraindication (travel less than 6 months earlier in ZIKA and malaria risk zone). NAT test performed in a under the SAE non-Eu recognized lab (US) was accepted as samples requested did not arrive in time • In all of them PCR + for covid is detected in the donor at the time of procurement and the procedure is stopped. Specification Other • Low cell count (under minimum required) (147) (cord blood) • Microbial contamination due to skin infection of patient (1 T&C affected) • Microbiological contamination of procured biological material • Number of cells in material released for transplantation < the value included in the Formal Request ( donor centre refused to perform another HSC separation) • SAE Specification • Positive microbiology results found after transplant (11) (cord blood) potentially inaccurate • Positive microbiology results found before transplant (137) (cord blood) • Post donation information : mutation not previously known in a recipient, discovered post allograft and post DLI; Polish donor positive for covid-19 (positive covid antigen test); positive Sars CoV-2 PCR performed on donor blood sample on the day of • Potentially not donation. reportable as SAE • Related donor with donation contraindication (recent piercing) was selected to donate PBSC (exceptional release). Tests for infectious disease markers to be performed on donor. • Related donor with donation contraindication (recent tattoo) was selected to donate PBSC (exceptional release). Tests for infectious • Insufficient disease markers to be performed on donor. information provided • Time or temperature exceeded • Without specification • Wrong or absent labelling • Not specified • Other ©2023 EDQM, Council of Europe. All rights reserved. 68  2023 SARE Exercise (2022 data) Distribution of SAE by Specification • 1% ( 7 out of 689) SAE were reported under the SAE Specification Human Error - Other, or no • Circuit break or leak of a pocket information to assign • Non-respect of the procedures for graft administration, loss of a few cells • Human error • Bacterial contamination. Product used • Leak noticed on stem cells bag due to poor quality seal. Product wasted. • A different SAE Specification could be assigned to each. ©2023 EDQM, Council of Europe. All rights reserved. 69  2023 SARE Exercise (2022 data) Distribution of SAE by Activity Step N=235 Distribution of SAE by Activity Step (2022 vs 2021) 235 vs 233 120 97 100 80 73 79 60 54 43 40 19 20 30 14 8 15 14 22 0 Human error System Tissue or cell Materials Other Equipment failure defect failure Reproductive T&C (2022) Reproductive T&C (2021) ©2023 EDQM, Council of Europe. All rights reserved. 70  2023 SARE Exercise (2022 data) Distribution of SAE by Specification N=235 Distribution of SAE by Specification (2022 vs 2021) 100 95 90 93 80 70 60 50 35 40 31 26 30 35 20 30 15 10 9 7 5 10 20 2 11 13 0 10 7 7 7 Reproductive T&C (2022) Reproductive T&C (2021) ©2023 EDQM, Council of Europe. All rights reserved. 71  2023 SARE Exercise (2022 data) Distribution of SAE by Activity Step and SAE Type N=235 0 10 20 30 40 50 60 70 80 90 100 Transport (10) 1 1 6 2 Donor selection (35) 25 2 5 3 Procurement (26) 8 11 9 6 1 Testing (9) 6 1 2 Processing (95) 2 5 10 18 54 6 Storage (7) 7 4 4 Product selection (5) 1 3 3 Same type of incidents classified Issue (5) 2 3 differently Distribution (2) 2 Other (31) 1 1 1 14 12 2 Tissue or cell defect Equipment failure Materials System failure Human error Other • Sperm, Embryo, Oocytes – Donor selection – T/C defect (11) (ES) • 54 SAE Human error (other, incorrect decision and following the wrong procedure) reported by 9 countries; • Oocytes, Embryo – Processing – Human error, Other (19) – material fail, culture contamination, handling incidents, non- compliance with prescription instructions (FR) • Oocytes, Embryo – Processing – System failure (15) – culture contamination, handling incidents, non-compliance with prescription instructions (FR) ©2023 EDQM, Council of Europe. All rights reserved. 72  2023 SARE Exercise (2022 data) Distribution of SAE by Specification 41% (97 out of 235) SAE were reported under the SAE Specification • Human Error - Incorrect decision following the right procedure (42) • Human Error - Following the wrong procedure (5) • Human error – Other (50) A different SAE Specification could be assigned to each of the 50 SAE Human error - Other . ©2023 EDQM, Council of Europe. All rights reserved. 73  2023 SARE Exercise (2022 data) Distribution of SAE by Specification • A straw of couple's semen is thawed but the donor oocytes had not been assigned and the cycle could not • 21% (50 out of 235) be performed. SAE were reported • Accident (overturning of a culture plate) during the observation of embryos, none of the four embryos being able to be recovered. under the SAE • Accident with devitrified oocyte plate due to the label being misplaced with the loss of 6 oocytes out of the Specification Human 12 that were present. Error - Other, or no • Accidental discard of the incorrect dish, resulting in a total loss of chance pf pregnancy for the cycle information to assign • Accidental loss of 4 oocytes due to drop of a microinjection plate resulting in a total loss of pregnancy for one cycle. • Accidental loss of all three oocytes collected • Accidental loss of nine embryos • A different SAE • Breaking of the cold chain in an oocyte support during handling for storage, affecting 2 oocytes. Specification could be • Cancellation of embryo transfer by thawing due to error of euploid embryo instead of aneuploid during assigned to each. thawing tasks of non-viable (aneuploid) embryos. • Contamination • Culture contamination • Defect during the identification process • Due to a power failure, 2 incubators containing embryos of 4 pairs are turned off and the embryos have to be discarded. • During embryo transfer, the only viable embryo is lost. There was excessive manipulation of the transfer catheter, as it was not possible cannulation of cervix on the first attempt. ©2023 EDQM, Council of Europe. All rights reserved. 74  2023 SARE Exercise (2022 data) Distribution of SAE by Specification – cont. • During the embryo reimplantation phase, the technologist released the catheter (containing the embryo) • 21% (50 out of 235) when leaving the airlock to bring it to the PMA gynaecologist. This is an extremely rare event and has never been encountered before at the fertility clinic. SAE were reported under the SAE • Embryo transfer failed. Embryo most likely lost in cervix/uterus by capillarity during physician insertion of the catheter into the uterus. Specification Human Error - Other, or no • Error in the blood group of the donor affecting 6 oocytes. information to assign • Failure to prepare culture plates. The lack of mineral oil in the plates facilitated the evaporation of the medium with the consequent increase in osmolarity and loss of cell viability. Loss of all embryos in the cycle • Handling incidents (excluding falls) • Material fall • A different SAE • Dish with embryo knocked over Specification could be • Non-compliance with prescription instruction assigned to each. • Pipetting error. Oocytes could not be located • Post-transmission infection • Retrieval of the ovarian tissue within a caesarean section. Contamination of the transport medium with skin germs Staph. Capitis, Epidermidis. The ovarian tissue had to be discarded • The collision of a pipette with the edge of the culture plate occurs, it fractures and the oocytes remain in the fractured part. The cycle had to be cancelled. • Tube with oocytes dropped after ovum pick-up • Wrong identification ©2023 EDQM, Council of Europe. All rights reserved. 75  2023 SARE Exercise (2022 data) Serious Adverse Reactions (in donors) 19 Countries: AT, BE, CZ, DE, EE, EL, ES, FI, FR, HR, IE, IT, LU, NL, NO, PL, PT, SE, and SE ©2023 EDQM, Council of Europe. All rights reserved. 76 SAR in Donors 2023 SARE Exercise (2022 data) Voluntary reporting SAR in donor by reporting countries and year 1000 17 17 900 19 17 19 800 19 21 700 19 17 600 18 500 934 903 846 400 795 777 700 710 300 620 622 547 200 394 100 104 0 2011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 SAR in donor Number of reporting countries ©2023 EDQM, Council of Europe. All rights reserved. 77 SAR in Donors 2023 SARE Exercise (2022 data) 2022 Replacement Haematopoietic Reproductive Total SAR in Country T&C Stem Cells T&C Donors 2021 Austria (AT) 1 10 11 Belgium (BE) 1 19 20 Croatia (HR) 11 11 Replacement Haematopoieti Reproductive Total SAR in Czechia (CZ) 112 112 Country T&C c Stem Cells T&C Donors Estonia (EE) 8 8 Finland (FI) 1 1 Belgium (BE) 2 17 19 France (FR) 12 274 286 Bulgaria (BG) 2 2 Germany (DE) 19 99 118 Croatia (HR) 3 3 Greece (EL) 2 2 Czechia (CZ) 84 84 Ireland (IE) 6 6 Estonia (EE) 5 5 Italy (IT) 5 6 11 Finland (FI) 2 2 Luxembourg (LU) 4 4 France (FR) 6 315 321 Netherlands (NL) 1 15 16 Germany (DE) 22 141 163 Norway (NO) 1 1 2 4 Greece (EL) 3 3 Poland (PL) 32 32 Ireland (IE) 7 7 Portugal (PT) 3 13 16 Italy (IT) 1 6 5 12 Slovenia (SI) 10 10 Netherlands (NL) 1 11 12 Spain (ES) 2 94 96 Poland (PL) 28 28 Sweden (SE) 1 10 11 Portugal (PT) 6 17 23 Slovenia (SI) 16 16 Total SAR 2 79 694 775 Spain (ES) 3 68 71 Sweden (SE) 24 24 Total 1 79 715 795 Replacement SAR in Donors: 1 infection = septic arthritis of knee after procurement of cartilage; 1 pain ©2023 EDQM, Council of Europe. All rights reserved. 78 SAR in Donors 2023 SARE Exercise (2022 data) HSC SAR in Donors by Type of HSC and Type of Reaction N= 79 Thrombotic / embolic (4) 4 Reactions other than 13 3 8 14 those listed above (38) Neurological disease (3) 1 2 Musculoskeletal / joint affection (1) 1 Mechanical damage (from apheresis 2 2 1 or bone marrow collection) (5) N= 79 2021 Infection (7) 1 6 General Autolo Allogenic Allogenic Reaction Type HSC gous related unrelated Autoimmune disease (7) 7 Acute systemic toxicity during mobilization or collection (8) 5 3 Allergic reaction (3) 2 1 Allergic reaction (2) 2 Autoimmune disease (9) 9 Infection (8) 1 7 Acute systemic toxicity during Mechanical damage (from apheresis or 8 4 mobilization or collection (12) bone marrow collection) (9) 6 1 1 1 Musculoskeletal / joint affection (1) 1 0 5 10 15 20 25 30 35 40 Neurological disease (2) 2 Reactions other than listed above (28) 13 3 3 9 General HSC Autologous Allogenic related Allogenic unrelated Thrombotic / embolic (11) 7 1 1 2 ©2023 EDQM, Council of Europe. All rights reserved. 79 SAR in Donors 2023 SARE Exercise (2022 data) HSC Reactions other than those listed • Atrial fibrillation during cytapheresis (harvesting of CAR T cells), death 2 days above post-procurement, splenic rupture • Acute coronary syndrome • Sinus tachycardia • Fatality: syncope 10 days after donation. Cause of death unknown • Reaction to citrate (Severe hypocalcaemia) • Multiple cases of neoplasm >6 months after donation • Donor withdraw during mobilization step • Reaction to inadequate harvesting • Lipothymia corrected with medication and donation resumed • Anaemia • Vomiting • Hypertension, dyspnoea, chest pain, arm pain • Palpitations, hot flush, hypokalaemia • Presyncope • Partial hearing loss, tinnitus • Unexpected effects (rare, or not described in the literature) Acute systemic toxicity during • Citrate cytotoxicity (2 connections swapped while building cell separator) mobilization or collection Mechanical damage (from apheresis or • Haematoma at application and catheter site bone marrow collection) • Bleeding at puncture site of groin catheter after catheter removal Autoimmune disease, Infection, - Thrombotic / embolic ©2023 EDQM, Council of Europe. All rights reserved. 80 SAR in Donors 2023 SARE Exercise (2022 data) Reproductive T&C Sperm (3) Oocytes (644 ) 0% N= 694 93% Other Tissue Sub- Reproductive type Reaction Type SAR #/ % Tissues (47) 7% Oocytes OHSS 355 / 51% Surgical complications 181 / 26% Reactions other than above 40 / 6% N= 718 2021 Infection 44 / 6% Tissue Sub- Reaction Type SAR % Ovarian torsion 24 / 3% type # Sperm Reaction to anaesthetic 1 / 0% Oocytes OHSS 394 55 Reactions other than above 2 / 0% Surgical complications 186 26 Other Infection 4 / 0.6% Reactions other than 55 8 Reproductive above Surgical complications 28 / 4% tissues Infection 51 7 Reactions other than above 15 / 2% Ovarian torsion 29 4 Sperm Surgical complications 2 0 Other Male genital organ 1 0 reproductive cellulitis tissues ©2023 EDQM, Council of Europe. All rights reserved. 81 SAR in Donors 2023 SARE Exercise (2022 data) Reproductive T&C SAR in Donors by Type of Reactions in Oocytes N= 694 0 50 100 150 200 250 300 350 OHSS (355) 326 9 20 Surgical Complications (181) 143 22 16 Reactions other than above (40) 29 11 2 Infections (44) 36 6 N= 712 2021 Partner or Non- Ovarian torsion (24) 22 2 SAR Type autologous partner General OHSS (394) 352 13 29 Surgical Complications (184) 153 26 5 Partner or autologous Non-partner General Reactions other than above (55) 37 5 13 Infections (50) 42 1 7 Ovarian torsion (29) 21 8 Total 712 605 45 62 ©2023 EDQM, Council of Europe. All rights reserved. 82 SAR in Donors 2023 SARE Exercise (2022 data) Reproductive T&C Infection (44) Surgical complications (181) Other reactions (40) • Suspicion of pelvic infection: abdominal • Hemoperitoneum (124 / 68.5%) • Abdominal pain and swelling that required pain, sub-febrile state • Difficult urination and haematuria surgery or hospitalization • Suspicion of pelvic infection: abdominal following follicle puncture of oocytes; • Bleeding after oocyte aspiration pain, sub-febrile state, nausea, surgery: bladder coagulation and • Ovarian abscess after cell aspiration diarrhoea bladder irrigation Pain after oocyte aspiration • Purulent inflammation of the right Vagal reaction and nausea after oocyte • Bladder puncture during OPU ovary after oocyte retrieval. Patient aspiration • Intra-abdominal haemorrhage 2 days • Ectopic pregnancy recovered completely. after oocyte aspiration • Thrombosis • Abscess following oocyte harvesting • Suspected pulmonary embolism • Haematuria • Ovarian abscess, acute pyelonephritis, • Bladder injury, ovarian haematoma • Renal insufficiency pelvic abscess, pelvic infection, pelvic • Bleeding; ovarian abscess requiring • Pulmonary embolism peritonitis, pyosalpinx, salpingitis, tubo- salpingectomy • Anaphylactic shock ovarain abscess • Suspected ovarian haematoma • Jugular vein thrombosis • Infection post egg collection with • Pelvic pain hospitalization. IL2 • Bladder puncture that required surgery or hospitalization • SV tachycardia • Pelvic infection • Reaction to opioid analgesia (repeated • Bacterial infection fainting requiring hospitalization) • Infection • Pain • Required surgery • Venous bleeding ©2023 EDQM, Council of Europe. All rights reserved. 83 Fatalities in Donors 2023 SARE Exercise (2022 data) Reproductive N= 4 Country HSC T&C France (FR) 1 1 Germany (DE) 1 Spain (ES) 1 HSC The donor death is related to an autologous mononuclear cells collection for CAR T cells: atrial fibrillation occurred during cataphoresis evolving to death at 2 days post procurement. 1 fatality (67 years old male): syncope 10 days after autologous donation (apheresis). The patient had already been deceased when emergency physician arrived. Cause of death unknown. An autopsy has not been performed. Reporter (Blood donation centre) assesses causality as unlikely. (DE) Reproductive T&C 1 fatality during anaesthetic induction (anaphylactic shock) for oocyte retrieval for ART (partner donor) Severe hemoperitoneum after puncture performed for fertility preservation in a patient diagnosed with aplasia medulla with lymphopenia and thrombopenia. Laparotomy for oophorectomy is performed. Leukopenia leads to sepsis which ends in death. ©2023 EDQM, Council of Europe. All rights reserved. 84 Fatalities in Recipients / Offspring 2023 SARE Exercise (2022 data) N= 12 Replacement Reproductive Tissues & Cells HSC Tissues & Cells Country SAR SAR SAR France (FR) 5 Germany (DE) 1 Spain (ES) 6 2021 Total = 12 1 5 6 Haematopoietic Reproductive Country Stem Cells T&C SAR SAE SAR Belgium (BE) 1 Czechia (CZ) 3 France (FR) 10 1 Germany (DE) 1 Poland (PL) 3 Spain (ES) 1 Total = 20 15 1 4 ©2023 EDQM, Council of Europe. All rights reserved. 85 Fatalities in Recipients 2023 SARE Exercise (2022 data) Replacement T&C N=1 • 1 fatality 6 years after heart valve transplant; underlying condition: congenital aortic stenosis. Cause of death: acute cardiac circulatory failure. Autopsy result: acute cardiac circulatory failure with almost complete avulsion of the left posterior aortic valve pocket with severe, calcifying degeneration of the aortic valve replacement with verrucous endocarditis. Blood cultures were negative. No deviations in donor documentation or processing. (IL1) (DE) ©2023 EDQM, Council of Europe. All rights reserved. 86 Fatalities in Recipients 2023 SARE Exercise (2022 data) Hematopoietic Stem Cells N=5 • 1 fatality (60 years old female) after peripheral blood stem cell transplant (PBSCT) recommended as treatment for myelofibrosis; the patient developed thrombocytopenia resistant to transfusion; cause of death: massive cerebral hemorrhage. (IL1) (FR) • 1 fatality (63 years old female) 10 months after PBSCT administered as treatment for immature acute myeloblastic leukemia with abnormal karyotype. 9 months after the graft, occurrence of various infections (cryptosporidiosis, enterococcus faecium treated with antibiotics) and then thrombotic microangiopathy with deep thrombocytopenia, renal failure and disturbances of consciousness. The patient died due to aggravation of thrombotic microangiopathy syndrome. (IL2) (FR) • 1 fatality (68 years old female) after PBSCT as treatment of 5q myelodysplasia and non-progressive B chronic lymphocytic leukemia. Aplasia resolved 1 month later but without transfusion independency. Cause of death: leukemia relapse. (FR) • 1 fatality (55 years old female) two months after PBSCT prescribed as treatment of refractory acute myeloid leukemia. Note: The recipient was covid positive 15 days before the graft with a lung positive picture; treatment for COVID-19 (Paxlovid+Xevudy) was administered prior to the graft. Aplasia resolved 25 days post graft. Treatment for GVHD prevention was instituted. However, the patient developed an acute cutaneous, digestive, oral and hepatic GVHD and multiple infections including Mucor mycosis (IL1) (FR) • 1 fatality (65 years old female) three days after autologous PBSCT performed to treat the relapse of an Ig A kappa mixed myeloma at stage III. At 3 days post graft, occurrence of diarrhea with blood, hypotension, renal failure and aplasia. A neutropenic colitis was diagnosed and the TDM indicated abdominal necrosis and abdominal chocks. Cause of death: neutropenic colitis (IL1) (FR) ©2023 EDQM, Council of Europe. All rights reserved. 87 Fatalities in Offspring 2023 SARE Exercise (2022 data) Reproductive T & C N=6 • Diamniotic monochorionic pregnancy in which the second foetus presented a malformation of the central nervous system that suggested vascular origin. The karyotype of both twins was normal. A caesarean section was scheduled, and the second twin presented an Apgar score of 0/0. A genetic study was not carried out on the donor since the pathology suggested vascular origin (IL1) (ES) • Voluntary interruption of pregnancy due to type II Arnold Chiari malformation, hydrocephalus and spina bifida (IL1) (ES) • Voluntary termination of twin pregnancy due to detection of 1q21.1 deletion of the RBM8A gene, which causes TAR syndrome, which is present in both foetuses and in the donor. The donor was blocked (ES) • Legal interruption of pregnancy due to foetal malformation with unbalanced chromosome endowment. Despite being considered de novo, the donor was blocked (ES) • Voluntary termination of pregnancy at week 12 due to foetus having multiple malformations. Donors were blocked (ES) • Sudden death of 1 of the 5 children born carriers of the SCN5A gene variant associated with severe heart rhythm disturbance. The children and the sperm donor carry the same variant. (IL3) (ES) Investigation conducted? Cause(s)? Actions? ©2023 EDQM, Council of Europe. All rights reserved. 88  2023 SARE Exercise (2022 data) Annual comparison (Years of exercises 2013-2023): number of units processed/distributed/recipients (mil.) 5.00 4.50 4.00 3.50 3.00 2.50 2.00 1.50 1.00 0.50 0.00 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 Recipients (mil.) 0.177 0.209 0.333 0.365 0.318 0.302 0.361 0.300 0.245 0.318 0.328 Units Distributed (mil.) 0.71 1.31 1.16 2.10 2.13 1.00 0.99 1.36 1.12 1.19 0.96 Units Processed (mil.) 0.89 1.55 1.43 2.28 1.77 1.86 2.58 2.92 2.65 3.16 2.89 Units Processed (mil.) Units Distributed (mil.) Recipients (mil.) ©2023 EDQM, Council of Europe. All rights reserved. 89  2023 SARE Exercise (2022 data) Annual comparison (Years of exercises 2013-2023): SAR, SAE, SAR in donors and fatalities 2500 2000 1500 1000 500 0 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 Fatalities in recipients/offspring 3 7 15 1 0 16 20 12 SAR in Donors 394 547 620 622 700 710 934 903 846 795 777 SAE 499 441 551 622 769 756 739 949 910 694 1,133 SAR 138 203 190 246 221 232 232 306 350 326 347 SAR SAE SAR in Donors Fatalities in recipients/offspring ©2023 EDQM, Council of Europe. All rights reserved. 90  2023 SARE Exercise (2022 data) Constant participation in SARE exercises The lower number of units distributed comparing to the previous four years is due to a reduction in the total number of distributed reproductive T&C (a significantly lower number of units of embryos reported). Reporting of denominators and imputability remain an issue. 8 countries report sparingly or never report any SAR or SAE. High variability among countries in terms of SAR/SAE reporting style (improvement required in terms of data completeness) Reporting of SAE – multiple issues: potentially not reportable SAE (PT) explain the high number of SAR in 2022; the proportion of categories Human error and Other remains very high, especially in SAR related to reproductive T&C; the sub category Human error – other is problematic; information provided regarding the events and course of action is insufficient; the SAE specification assigned is not always accurate Aspects specific to MAR procedures: reporting of transmitted infections associated with MAR procedures requires improvement (no relevant information provided in 2022); the percentage of uncategorized SAR remains very high (49%) Requirements for reporting fatalities in recipients as stated in the Common Approach largely not met, especially for IL3 SAR where an investigation should be conducted, and the results and actions implemented reported. The distribution of SAR in donors among the 3 categories of T&C remained unchanged in 2022; 4 fatalities in donors were reported this year; imputability of one was assessed as unlikely. ©2023 EDQM, Council of Europe. All rights reserved. 91  2023 SARE Exercise (2022 data) Next step 2023 SARE exercise (data 2022) Summary Report [email protected] ©2023 EDQM, Council of Europe. All rights reserved. 92  Thank you for your attention Stay connected with the EDQM EDQM Newsletter: https://go.edqm.eu/Newsletter LinkedIn: https://www.linkedin.com/company/edqm/ Twitter: @edqm_news Facebook: @EDQMCouncilofEurope ©2020 EDQM, Council of Europe. All rights reserved.