Innocuité de la substitution et de l’interchangeabilité des … · 2020-06-01 · Le présent document contient les annexes complémentaires au rapport Innocuité de la substitution

Innocuité de la substitution et de

l’interchangeabilité des médicaments

biologiques Annexes complémentaires

ÉTAT DES CONNAISSANCES

MAI 2020

Une production de l’Institut national d’excellence en santé et en services sociaux (INESSS)

B

Innocuité de la substitution et de

l’interchangeabilité des médicaments

biologiques Annexes complémentaires

Le présent document contient les annexes complémentaires au rapport Innocuité de la substitution et de l’interchangeabilité des médicaments biologiques. Le contenu de cette publication a été rédigé et édité par l’INESSS.

Ces annexes et le rapport final sont accessibles en ligne dans la section Publications de notre site Web.

Renseignements

Institut national d’excellence en santé et en services sociaux (INESSS)

2535, boulevard Laurier, 5e étage

Québec (Québec) G1V 4M3

Téléphone : 418 643-1339

Télécopieur : 418 646-8349

2021, avenue Union, bureau 10.083

Montréal (Québec) H3A 2S9

Téléphone : 514 873-2563

Télécopieur : 514 873-1369

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Responsabilité

L’Institut rend accessibles les principales informations qui ont servi à l’état des connaissances sur les Stratégies de cessation tabagique aux lecteurs qui désirent plus de détails sur sa démarche scientifique. Ce document n’a pas fait l’objet d’une révision linguistique. Il ne reflète pas forcément les opinions des autres personnes consultées aux fins du présent dossier.

i

TABLE DES MATIÈRES

ANNEXE A ............................................................................................................................................ 1

Stratégies de repérage de l’information scientifique ............................................................................ 1

ANNEXE B ............................................................................................................................................ 3

Sélection des documents et listes et raisons des exclusions .............................................................. 3

ANNEXE C .......................................................................................................................................... 18

Évaluation de la qualité méthodologique des documents .................................................................. 18

ANNEXE D .......................................................................................................................................... 35

Caractéristiques des études primaires retenues ................................................................................ 35

ANNEXE E ........................................................................................................................................ 169

Tableaux de résultats ....................................................................................................................... 169

ANNEXE F ........................................................................................................................................ 270

Appréciation de la preuve scientifique ............................................................................................. 270

REFERENCES ....................................................................................................................................... 290

ii

LISTE DES TABLEAUX

Tableau B1 – Liste des documents exclus ................................................................................................. 4

Tableau B2 – Liste des documents inclus .................................................................................................. 6

Tableau C1 – Évaluation des études primaire : Grille ASPC ................................................................... 18

Tableau C1 – Évaluation des études primaire : Grille ASPC (suite 1) ..................................................... 19







Tableau C2 – Évaluation des guides de pratique clinique retenus (AGREE-GRS) ................................. 26

Tableau C3 – Résumé de l’évaluation AACODS pour les énoncés de position retenus ......................... 27

Tableau C3 – Résumé de l’évaluation AACODS pour les énoncés de position retenus (suite 1) ........... 29



Tableau D1 – Caractéristiques de Abdalla 2017 ...................................................................................... 35

Tableau D2 – Caractéristiques de Alten 2019 .......................................................................................... 36

Tableau D3 – Caractéristiques de Argüelles-Arias 2017 .......................................................................... 38

Tableau D4 – Caractéristiques de Avouac 2018 ...................................................................................... 40

Tableau D5 – Caractéristiques de Belleudi 2019 ..................................................................................... 41

Tableau D6 – Caractéristiques de Benucci 2017 ..................................................................................... 43

Tableau D7 – Caractéristiques de Bergqvist 2018 ................................................................................... 44

Tableau D8 – Caractéristiques de Blackwell 2018 ................................................................................... 46

Tableau D9 – Caractéristiques de Blauvelt 2018 ..................................................................................... 48

Tableau D10 – Caractéristiques de Blevins 2019..................................................................................... 50

Tableau D11 – Caractéristiques de Bonifati 2019 .................................................................................... 52

Tableau D12 – Caractéristiques de Bronswijk 2020 ................................................................................. 54

Tableau D13 – Caractéristiques de Buer 2017 ......................................................................................... 55

Tableau D14 – Caractéristiques de Cohen 2020...................................................................................... 57

Tableau D15 – Caractéristiques de Cohen 2018...................................................................................... 59

Tableau D16 – Caractéristiques de Eberl 2017 ........................................................................................ 62

Tableau D17 – Caractéristiques de Emery 2017 ...................................................................................... 63

Tableau D18 – Caractéristiques de Fabiani 2019 .................................................................................... 65

Tableau D19 – Caractéristiques de Felis-Giemza 2019 ........................................................................... 66

Tableau D20 – Caractéristiques de Fiorino 2018 ..................................................................................... 68

Tableau D21 – Caractéristiques de Genovese 2019 ................................................................................ 69

Tableau D22 – Caractéristiques de Gervais 2018 .................................................................................... 71

Tableau D23 – Caractéristiques de Glintborg 2019.................................................................................. 73

iii

Tableau D24 – Caractéristiques de Glintborg 2017.................................................................................. 74

Tableau D25 – Caractéristiques de Goll 2019 .......................................................................................... 76

Tableau D26 – Caractéristiques de Griffiths 2017 .................................................................................... 78

Tableau D27 – Caractéristiques de Guerra Veloz 2019 ........................................................................... 81

Tableau D28 – Caractéristiques de Guerra Veloz (REED) 2018 ............................................................. 83

Tableau D29 – Caractéristiques de Guerra Veloz 2018 (WJG) ............................................................... 84

Tableau D30 – Caractéristiques de Guerrero Puente 2017 ..................................................................... 86

Tableau D31 – Caractéristiques de Guiotto 2019..................................................................................... 87

Tableau D32 – Caractéristiques de Haag-Weber 2009 ............................................................................ 89

Tableau D33 – Caractéristiques de Hadjiyianni 2016 .............................................................................. 90

Tableau D34 – Caractéristiques de Hercogova 2020 ............................................................................... 92

Tableau D35 – Caractéristiques de Hoivik 2018 ...................................................................................... 94

Tableau D36 – Caractéristiques de Jaworski 2019 .................................................................................. 95

Tableau D37 – Caractéristiques de Jorgensen 2017 ............................................................................... 98

Tableau D38 – Caractéristiques de Kaltsonoudis 2019 ......................................................................... 101

Tableau D39 – Caractéristiques de Kang 2018 ...................................................................................... 102

Tableau D40 – Caractéristiques de Kolar 2017 ...................................................................................... 103

Tableau D41 – Caractéristiques de Lukas 2020..................................................................................... 105

Tableau D42 – Caractéristiques de Matsuno 2019 ................................................................................ 106

Tableau D43 – Caractéristiques de Minutolo 2017................................................................................. 108

Tableau D44 – Caractéristiques de Nikiphorou 2015 ............................................................................. 109

Tableau D45 – Caractéristiques de Papp 2017 ...................................................................................... 111

Tableau D46 – Caractéristiques de Park 2017 (CT-P10) ....................................................................... 113

Tableau D47 – Caractéristiques de Park 2017 (CT-P13) ....................................................................... 115

Tableau D48 – Caractéristiques de Pescitelli 2019 ................................................................................ 117

Tableau D49 – Caractéristiques de Petitdidier 2019 .............................................................................. 118

Tableau D50 – Caractéristiques de Plevris 2019 ................................................................................... 120

Tableau D51 – Caractéristiques de Ratnakumaran 2018 ...................................................................... 121

Tableau D52 – Caractéristiques de Razanskaite 2017 .......................................................................... 122

Tableau D53 – Caractéristiques de Rosenstock 2015 ........................................................................... 123

Tableau D54 – Caractéristiques de Scherlinger 2018 ............................................................................ 126

Tableau D55 – Caractéristiques de Schmitz (APT) 2017 ....................................................................... 127

Tableau D56 – Caractéristiques de Schmitz 2018 ................................................................................. 128

Tableau D57 – Caractéristiques de Shim 2019 ...................................................................................... 129

Tableau D58 – Caractéristiques de Sieczkowska 2016 ......................................................................... 131

Tableau D59 – Caractéristiques de Smits 2019 ..................................................................................... 132



Tableau D62 – Caractéristiques de Smolen 2018 .................................................................................. 136

iv

Tableau D63 – Caractéristiques de Strik 2018 ....................................................................................... 138

Tableau D64 – Caractéristiques de Tanaka 2016 .................................................................................. 140

Tableau D65 – Caractéristiques de Thadhani 2018 ............................................................................... 143

Tableau D66 – Caractéristiques de Tony 2019 ...................................................................................... 146

Tableau D67 – Caractéristiques de Tweehuysen 2018a ........................................................................ 148

Tableau D68 – Caractéristiques de Tweehuysen 2018b ........................................................................ 150

Tableau D69 – Caractéristiques de Van Hoeve 2019 ............................................................................ 152

Tableau D70 – Caractéristiques de Vergara-Dangond 2017 ................................................................. 153

Tableau D71 – Caractéristiques de Von Minckwitz 2018 ....................................................................... 155

Tableau D72 – Caractéristiques de Weinblatt 2018 ............................................................................... 157

Tableau D73 – Caractéristiques de Yamanaka 2020 ............................................................................. 159

Tableau D74 – Caractéristiques de Yazici 2018..................................................................................... 161

Tableau D75 – Caractéristiques de Ye 2019 .......................................................................................... 163

Tableau D76 – Caractéristiques de Yoo 2017 ........................................................................................ 167

Tableau E1 – Perte d’efficacité – Maladie de Crohn .............................................................................. 169

Tableau E2 – Perte d’efficacité – Colite Ulcéreuse ................................................................................ 172

Tableau E3 – Perte d’efficacité – Maladie inflammatoire de l’intestin (MC, CU, MII non classée) ......... 174

Tableau E4 – Immunogénicité – Maladie de Crohn ............................................................................... 177

Tableau E5 – Immunogénicité – Maladie inflammatoire de l’intestin (MC, CU, MII non classée) .......... 178

Tableau E6 – Effets indésirables – Maladie de Crohn ………………………………………………….… 179

Tableau E7 – Effets indésirables – Colite ulcéreuse .............................................................................. 181

Tableau E8 – Effets indésirables – Maladie inflammatoire de l’intestin (MC, CU, MII non classée) ...... 182

Tableau E9 – Rétention – Maladie de Crohn .......................................................................................... 184

Tableau E10 – Rétention – Colite ulcéreuse .......................................................................................... 186

Tableau E11 – Rétention – Maladie inflammatoire de l’intestin (MC, CU) ............................................. 187

Tableau E12 – Perte d’efficacité – Polyarthrite rhumatoïde ................................................................... 188

Tableau E13 – Perte d’efficacité – Spondylarthrite ankylosante ............................................................ 192

Tableau E14 – Perte d’efficacité – Arthrite psoriasique .......................................................................... 195

Tableau E15 – Perte d’efficacité – Arthrite inflammatoire (PR, SA, AP) ................................................ 196

Tableau E16 – Immunogénicité – Polyarthrite rhumatoïde .................................................................... 198

Tableau E17 – Innocuité – Polyarthrite rhumatoïde ............................................................................... 203

Tableau E18 – Innocuité – Spondylarthrite ankylosante ........................................................................ 209

Tableau E19 – Innocuité – Arthrite inflammatoire (PR, SA, AP) ............................................................ 210

Tableau E20 – Rétention – Polyarthrite rhumatoïde .............................................................................. 212

Tableau E21 – Rétention – Spondylarthrite ankylosante ....................................................................... 217

Tableau E22 – Rétention – Arthrite psoriasique ..................................................................................... 218

Tableau E23 – Rétention – Arthrite inflammatoire (PR, SA, AP) ............................................................ 219

Tableau E24 – Perte d’efficacité – Psoriasis en plaque ......................................................................... 222

Tableau E25 – Immunogénicité – Psoriasis en plaque .......................................................................... 225

v

Tableau E26 – Innocuité – Psoriasis en plaque ..................................................................................... 229

Tableau E27 – Rétention – Psoriasis en plaque..................................................................................... 235

Tableau E28 – Immunogénicité – Spécialités combinées ...................................................................... 239

Tableau E29 – Innocuité – Spécialités combinées ................................................................................. 240

Tableau E30 – Rétention – Spécialités combinées ................................................................................ 241

Tableau E31 – Perte d’efficacité – Oncologie ......................................................................................... 242

Tableau E32 – Immunogénicité – Oncologie .......................................................................................... 243

Tableau E33 – Innocuité – Oncologie ..................................................................................................... 244

Tableau E34 – Rétention – Oncologie .................................................................................................... 246

Tableau E35 – Perte d’efficacité – Diabète ............................................................................................ 248

Tableau E36 – Immunogénicité – Diabète .............................................................................................. 251

Tableau E37 – Innocuité – Diabète ........................................................................................................ 254

Tableau E38 – Rétention – Diabète ........................................................................................................ 257

Tableau E39 – Perte d’efficacité – Hématologie/Néphrologie ................................................................ 258

Tableau E40 – Immunogénicité – Hématologie/Néphrologie ................................................................. 261

Tableau E41 – Innocuité – Hématologie/Néphrologie ............................................................................ 262

Tableau E42 – Rétention – Hématologie/Néphrologie ........................................................................... 264

Tableau E43 – Effets indésirables – Changement de traitement d’un BR vers un BS - Études sans comparateur ................................................................................................................... 266

Tableau F1 – Critères d’appréciation de la qualité de la preuve scientifique ......................................... 270

Tableau F2 – Appréciation de la preuve pour la Gastroentérologie ....................................................... 272

Tableau F3 – Appréciation de la preuve pour la Rhumatologie ............................................................. 275

Tableau F4 – Appréciation de la preuve pour la Dermatologie .............................................................. 278

Tableau F5 – Appréciation de la preuve pour l’Oncologie (prévention de la neutropénie) .................... 280

Tableau F6 – Appréciation de la preuve pour l’Oncologie (cancer du sein, HER2 positif) .................... 282

Tableau F7 – Appréciation de la preuve pour la Hématologie/Néphrologie ........................................... 284

Tableau F8 – Appréciation de la preuve pour l’Endocrinologie (Diabète) .............................................. 286

Tableau F9 – Appréciation de la preuve pour des substitutions multiples ............................................. 288

LISTE DES FIGURES

Figure B1 - Diagramme de flux................................................................................................................ 3

I

SIGLES ET ABRÉVIATIONS

AACE/ACE American Association of Clinical Endocrinologists and American

College of Endocrinology

AAD American Academy of Dermatology Association

AACODS Authority, accuracy, coverage, objectivity, date and significance

ACD Association canadienne de dermatologie

ACR American College of Rheumatology

AGES Austria Medecines and Medical Devices Agency

AGREE-GRS Appraisal of guidelines for research and evaluation, Global Rating Scale

AP Arthrite psoriasique

ASCO American Society of Clinical Oncology

ASPC Agence de la santé publique du Canada

BC Cancer British Columbia Cancer

BIRD Belgium Inflammatory Bowel Disease Research and Development Group

BR Médicament biologique de référence

BS Médicament biosimilaire

BSR Brazilian Society of Rheumatology

CAG-CCC Canadian Gastroenterology Association et Crohn’s Colitis Canada

CU Colite ulcéreuse

DT1 Diabète de type 1

DT2 Diabète de type 2

EBE European Biopharmaceutical Enterprises

ECCO European Crohn’s and Colitis Organisation

ECRA Essai comparatif à répartition aléatoire

ENCAA Essai non contrôlé avant après

EI Effets indésirables

EIAT Effets indésirables apparus en cours de traitement

EIG Effets indésirables graves

EIGAT Effets indésirables graves apparus en cours de traitement

EMA European Medicines Agency

ESMO European Society for Medical Oncology

ESPGHAN European Society for Pediatric Gastroenterology, Hepatology and Nutrition

EULAR European League Against Rheumatism-People with Arthritis and Rheumatism

FDA Food and Drug Administration (États-Unis)

GPC guide de pratique clinique

HAS Haute Autorité de Santé (France)

HIS Healthcare Improvement Scotland (HIS)

HKSR Hong Kong Society of Rheumatology

IG-IBD Italian Group for Inflammatory Bowel Disease

II

INESSS Institut d’excellence en santé et en services sociaux

ISOPP International Society of Oncology Pharmacy Practitioners

MC Maladie de Crohn

MII Maladies inflammatoires de l’intestin

MIInc Maladies inflammatoires de l’intestin, non classées

NICE National Institute for Health and Care Excellence (Royaume-Uni)

NRAS National Rheumatoid Arthritis Society (Royaume-Uni)

PNCG Polish National Consultant in Gastroenterology

PR Polyarthrite rhumatoïde

Ps Psoriasis en plaques

SA Spondylarthrite ankylosante

SAMAC South Australia Medicines Advisory Committee

SBOC Brazilian Health Surveillance Agency

SCR Société canadienne de rhumatologie

SEFH Sociedad Espanola de Farmacia Hospitalaria

SFDA Saudi Food and Drug Authority

TNF Facteur de nécrose tumorale

1

ANNEXE A

Stratégies de repérage de l’information scientifique

Bases de données bibliographiques

PubMed (NLM) Date du repérage : décembre 2019 Limites : anglais, français

#1

biosimilar*[tiab] OR bio-similar*[tiab] OR reference product*[tiab] OR reference biologic*[tiab] OR originator*[tiab] OR biological medicine*[tiab] OR biological drug*[tiab] OR biological product*[tiab] OR biologic medicine*[ti] OR biologic drug*[ti] OR biologic product*[ti] OR biomedicament*[ti] OR biologic agent*[ti] OR biopharmaceut*[ti] OR biomedicine*[ti]

#2 switch*[tiab] OR interchang*[tiab] OR substitut*[tiab]

#3 #1 AND #2

#4 guideline*[tiab] OR consensus[tiab] OR position statement*[tiab]

#5 #1 AND #4

#6 #3 OR #5

#7 animal*[tiab] OR mouse[tiab] OR mice[tiab] OR rat[tiab] OR rats[tiab] OR monkey*[tiab] OR rabbit*[tiab]

#8 #6 NOT #7

#9 case report*[tw] OR case serie*[tw] OR case stud*[tw] OR comment[tw] OR editorial[tw] OR letter[tw]

#10 #8 NOT #9

Embase (Ovid) Date du repérage : décembre 2019 Limites : anglais, français; embase; exclusion périodiques medline

1 (biosimilar* OR bio-similar* OR (reference ADJ2 (product* OR biologic*)) OR (biological ADJ2 (medicine* OR drug* OR product*)) OR originator*).ti,ab OR ((biologic ADJ2 (medicine* OR drug* OR product* OR agent*)) OR biomedicament* OR biopharmaceut* OR biomedicine*).ti

2 (switch* OR interchang* OR substitut*).ti,ab

3 1 AND 2

4 (guideline* OR consensus OR position statement*).ti,ab

5 1 AND 4

6 3 OR 5

7 (animal* OR mouse OR mice OR rat OR rats OR monkey* OR rabbit*).ti,ab

8 6 NOT 7

9 (case report* OR case serie* OR case stud* OR comment OR editorial OR letter).ti,ab

10 8 NOT 9

EBM Reviews (Ovid) : Cochrane Database of Systematic Reviews; Database of Abstracts of Reviews of Effects; Health Technology Assessment; NHS Economic Evaluation Database Date du repérage : décembre 2019 Limites : anglais, français

1 (biosimilar* OR bio-similar* OR (reference ADJ2 (product* OR biologic*)) OR (biological ADJ2 (medicine* OR drug* OR product*)) OR originator*).ti,ab OR ((biologic ADJ2 (medicine* OR drug* OR product* OR agent*)) OR biomedicament* OR biopharmaceut* OR biomedicine*).ti

2 (animal* OR mouse OR mice OR rat OR rats OR monkey* OR rabbit*).ti,ab

3 1 NOT 2

2

Sites Web, registres d’essais cliniques, moteurs de recherche et autres bases de données Date de la consultation : décembre 2019 Limites : anglais et français

• Academic Pediatric Association (https://www.academicpeds.org/)

• Alberta Health (www.alberta.ca/biosimilar-drugs)

• American Academy of Allergy Asthma & Immunology (https://www.acaai.org)

• American Academy of Dermatology Association (https://www.aad.org/)

• American Association of Clinical Endocrinologists (https://www.aace.com/)

• American association of immunologist (https://www.aai.org/)

• American College of Physicians (https://www.acponline.org/)

• American College of Rheumatology (https://www.rheumatology.org)

• American Gastroenterological Association (https://www.gastro.org/)

• American Medical Association (https://www.ama-assn.org/)

• American Pharmacists Association (https://www.pharmacist.com/)

• American Society of Clinical Oncology (https://www.asco.org/)

• ASBM, Alliance for Safe Biologic Medicines (https://safebiologics.org/)

• Association canadienne de dermatologie (https://dermatology.ca/fr/)

• BC Cancer (http://www.bccancer.bc.ca/)

• BC Pharmacare (https://www2.gov.bc.ca/gov/content/health/)

• Canadian Association of Medical Oncologists (https://camo-acom.ca/)

• Canadian Hematology Society (https://canadianhematologysociety.org/)

• Canadian Society for Immunology (https://www.csi-sci.ca/)

• Cancer Care Ontario, (https://www.smartbiggar.ca/insights/publication/update-on-biosimilars-in-canada-october-2019) (http://www.health.gov.on.ca/en/pro/programs/drugs/opdp_eo/notices/fq_exec_office_20170731.pdf) (http://www.health.gov.on.ca/en/pro/programs/drugs/opdp_eo/notices/fq_exec_office_20160311_1.pdf) (http://www.health.gov.on.ca/en/pro/programs/drugs/opdp_eo/notices/fq_exec_office_20180920_2.pdf)

• ClinicalTrials.gov (clinicaltrials.gov/)

• Diabète Canada (https://www.diabete.qc.ca/fr)

• European Academy of Dermatology (https://www.eadv.org/)

• European Crohn’s Colitis Organization (https://www.ecco-ibd.eu/)

• European Federation of Immunological Societies (https://www.efis.org/)

• European League Against Rheumatism – EULAR (https://www.eular.org/)

• European Society of Endocrinology (https://www.ese-hormones.org/)

• FDA (https://www.fda.gov)

• Generic and Biosimilars initiative (http://gabi-journal.net/what-pricing-and-reimbursement-policies-to-use-for-off-patent-biologicals-in-europe-results-from-the-second-ebe-biological-medicines-policy-survey.html) (www.gabionline.net/Reports/Biosimilar-substitution-in-Europe) (https://www.centerforbiosimilars.com/conferences/biotech-pharma-summit-biosimilars/regulator-explains-how-denmark-has-achieved-its-biosimilar-success) (http://gabionline.net/Reports/International-policies-for-interchangeability-switching-and-substitution-of-biosimilars)

• Gouvernement du Nouveau-Brunswick (https://www2.gnb.ca/content/dam/gnb/Departments/h-s/pdf/en/NBDrugPlan/NewBrunswickDrugPlansFormulary.pdf)

• Green Shield (https://www.greenshield.ca/en-ca)

• HAS (https://www.has-sante.fr/)

• International Clinical Trials Registry Platform Search Portal (WHO) (http://apps.who.int/trialsearch/)

• International Society of Oncology Pharmacy Practitioners – ISOPP (https://www.isopp.org/)

• NHS (https://www.nhs.uk/)

• NICE (https://www.nice.org.uk/)

• SAMAC (https://www.sahealth.sa.gov.au/)

• Société canadienne d’endocrinologie et de métabolisme (https://www.endo-metab.ca/)

• Société canadienne de rhumatologie (https://rheum.ca/fr/)

• United European Gastroenterology (https://www.ueg.eu/)

3

ANNEXE B

Sélection des documents et listes et raisons des exclusions

Figure B1 - Diagramme de flux

Enregistrements repérés dans les bases de données (n =1677)

Enregistrements repérés dans d’autres sources

(n = 72)

Enregistrements retirés (doublons) (n = 114)

Enregistrements sélectionnés (n = 1635)

Enregistrements exclus (n = 1490)

Publications complètes évaluées (n = 145) Articles complets exclus,

avec les raisons (n = 32)

Doublon, n = 2 Devis inadéquat, n = 2 Absence de résultats d’intérêt, n = 28

Publications incluses (n = 113)

Articles primaire, n = 76

GPC, n = 4 Énoncé de position, n = 33

Rep

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S

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Inclu

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4

Tableau B1 – Liste des documents exclus

Auteur, Année Titre Raison

d’exclusion

Alliance for Safe Biologic Medicines

Fact sheets: Biosimilar Substitution Absence des résultats d’intérêt

Argüelles-Arias, F., et al. Effectiveness and Safety of CT-P13 (Biosimilar Infliximab) in Patients with Inflammatory Bowel Disease in Real Life at 6 Months

Doublon

Ampudia-Blasco, F. J. Biosimilars and Novel Insulins Absence des résultats d’intérêt

Chingcuanco, F., et al. Bioequivalence of Biosimilar Tumor Necrosis Factor-alpha Inhibitors Compared with Their Reference Biologics: A Systematic Review

Absence des résultats d’intérêt

Derwahl, K. M., et al. Efficacy and Safety of Biosimilar SAR342434 Insulin Lispro in Adults with Type 2 Diabetes, Also Using Insulin Glargine: SORELLA 2 Study.


Diabète Canada Diabetes, Biologic Drugs, and Biosimilar Insulins Devis inadéquat

Dormuth, C. R., et al. A rapid monitoring plan following a shift in coverage from brand name to biosimilar drugs for rheumatoid arthritis in British Columbia

Devis inadéquat

Flodmark, C. E., et al. Switching from Originator to Biosimilar Human Growth Hormone Using Dialogue Teamwork: Single-Center Experience From Sweden


Fonseca, J. E., et al. The Portuguese Society of Rheumatology position paper on the use of biosimilars

Doublon

Gerdes, S., et al. Multiple switches between GP2015, an etanercept biosimilar, with originator product do not impact efficacy, safety and immunogenicity in patients with chronic plaque-type psoriasis: 30-week results from the phase 3, confirmatory EGALITY study


Goncalves, J., et al. Antigenic response to CT-P13 and infliximab originator in inflammatory bowel disease patients shows similar epitope recognition


Hlavaty, T., et al. Biosimilar infliximab CT-P13 treatment in patients with inflammatory bowel diseases – a one-year, single-centre retrospective study


Hu, X., et al. Switching from biosimilar (Basalin) to originator (Lantus) insulin glargine is effective in Chinese patients with diabetes mellitus: A retrospective chart review

Biosimilaire non approuvé au

Canada

Huoponen, S., et al. Health-related quality of life and costs of switching originator infliximab to biosimilar one in treatment of inflammatory bowel disease


Ingrasciotta, Y., et al. In Search of Predictors of Switching Between Erythropoiesis-Stimulating Agents in Clinical Practice: A Multi-Regional Cohort Study


International Coalition of Medicines Regulatory Authorities

ICMRA statement about confidence in biosimilar products (for patients and the public)


Ilias, A., et al. Outcomes of Patients with Inflammatory Bowel Diseases Switched from Maintenance Therapy with a Biosimilar to Remicade®


Ito, H., et al. A comparison of the clinical courses of type 2 diabetic patients whose basal insulin preparation was replaced from insulin glargine 100 units/mL to insulin glargine biosimilar or 300 units/mL: A propensity score-matched observation study


Kolberg, H. C., et al. Cardiac Safety of the Trastuzumab Biosimilar ABP 980 in Women with HER2-Positive Early Breast Cancer in the Randomized, Double-Blind, Active-Controlled LILAC Study


Lee, S., et al. Comparative Efficacy and Safety of Biosimilar Rituximab and Originator Rituximab in Rheumatoid Arthritis and Non-Hodgkin's Lymphoma: A Systematic Review and Meta-analysis


Llag, L. L., et al. Evaluation of immunogenicity of LY2963016 insulin glargine compared with Lantus® insulin glargine in patients with type 1 or type 2 diabetes mellitus


Nguyen, E., et al. Impact of non-medical switching on clinical and economic outcomes, resource utilization and medication-taking behavior: A systematic literature review


NICE Biosimilar medicines Absence des résultats d’intérêt

Otha, S., et al. Efficacy of once or twice weekly administration of epoetin κ in patients receiving hemodialysis: A retrospective study


Panaccione, R., et al. Clinical practice guidelines: Canadian Association of Gastroenterology Clinical Practice Guideline for the Management of Luminal Crohn’s Disease


Rashid, N., et al. Switching to Omnitrope from Other Recombinant Human Growth Hormone Therapies: A Retrospective Study in an Integrated Healthcare System


Renton, W. D., et al. Same but different? A thematic analysis on adalimumab biosimilar switching among patients with juvenile idiopathic arthritis


5

Auteur, Année Titre Raison

d’exclusion

Segal, D., et al. The Biosulin equivalence in standard therapy (BEST) study − a multicentre, open-label, non-randomised, interventional, observational study in subjects using Biosulin 30/70 for the treatment of insulin-dependent type 1 and type 2 diabetes mellitus


Sharma, A., et al. Immunogenicity and efficacy after switching from original Ranibizumab to a Ranibizumab biosimilar: Real-world data


Stubbs, M. J., et al. Comparison of Rituximab originator (MabThera) to biosimilar (Truxima) in patients with immune-mediated thrombotic thrombocytopenic purpura


Verpoort, K., et al. A non-interventional study of biosimilar granulocyte colony-stimulating factor as prophylaxis for chemotherapy-induced neutropenia in a community oncology centre


Wiecek, A., et al. Switching Epoetin Alfa and Epoetin Zeta in Patients with Renal Anemia on Dialysis: Posthoc Analysis


6

Tableau B2 – Liste des documents inclus

Identification Référence Pathologie Molécule

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Articles primaires

Abdalla et al., 2017

Abdalla A, Byrne N, Conway R, Walsh T, Mannion G, Hanly M, et al. Long-term safety and efficacy of biosimilar infliximab among patients with inflammatory arthritis switched from reference product. Open Access Rheumatol 2017;9:29-35

PR, AP, SA Infliximab ENCAA ✓

Alten et al., 2019

Alten R, Batko B, Hala T, Kameda H, Radominski SC, Tseluyko V, et al. Randomised, double-blind, phase III study comparing the infliximab biosimilar, PF-06438179/GP1111, with reference infliximab: Efficacy, safety and immunogenicity from week 30 to week 54. RMD Open 2019;5(1):e000876

PR Infliximab ECRA ✓ ✓ ✓

Argüelles-Arias et al., 2017

Argüelles-Arias F, Guerra Veloz MF, Perea Amarillo R, Vilches-Arenas A, Castro Laria L, Maldonado Perez B, et al. Switching from reference infliximab to CT-P13 in patients with inflammatory bowel disease: 12 months results. Eur J Gastroenterol Hepatol 2017a;29(11):1290-5

MC, CU Infliximab ENCAA ✓

Avouac et al., 2018

Avouac J, Molto A, Abitbol V, Etcheto A, Salcion A, Gutermann L, et al. Systematic switch from innovator infliximab to biosimilar infliximab in inflammatory chronic diseases in daily clinical practice: The experience of Cochin University Hospital, Paris, France. Semin Arthritis Rheum 2018;47(5):741-8

PR, SA, MC, CU Infliximab ENCAA ✓

Belleudi et al., 2019

Belleudi V, Trotta F, Addis A, Ingrasciotta Y, Ientile V, Tari M, et al. Effectiveness and safety of switching originator and biosimilar epoetins in patients with chronic kidney disease in a large-scale Italian cohort study. Drug Saf 2019;42(12):1437-47

Anémie Epoetin Cohortes

rétrospectives ✓ ✓

Benucci et al., 2017

Benucci M, Gobbi FL, Bandinelli F, Damiani A, Infantino M, Grossi V, et al. Safety, efficacy and immunogenicity of switching from innovator to biosimilar infliximab in patients with spondyloarthritis: A 6-month real-life observational study. Immunol Res 2017;65(1):419-22

SA Infliximab ENCAA ✓

Bergqvist et al., 2018

Bergqvist V, Kadivar M, Molin D, Angelison L, Hammarlund P, Olin M, et al. Switching from originator infliximab to the biosimilar CT-P13 in 313 patients with inflammatory bowel disease. Therap Adv Gastroenterol 2018;11:1756284818801244


Blackwell et al., 2018

Blackwell K, Gascon P, Krendyukov A, Gattu S, Li Y, Harbeck N. Safety and efficacy of alternating treatment with EP2006, a filgrastim biosimilar, and reference filgrastim: A phase III, randomised, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy. Ann Oncol 2018;29(1):244-9

Neutropénie Filgrastim ECRA ✓ ✓ ✓ ✓

7


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Blauvelt et al., 2018

Blauvelt A, Lacour JP, Fowler JF Jr, Weinberg JM, Gospodinov D, Schuck E, et al. Phase III randomized study of the proposed adalimumab biosimilar GP2017 in psoriasis: Impact of multiple switches. Br J Dermatol 2018;179(3):623-31

Ps Adalimumab ECRA ✓ ✓ ✓

Blevins et al., 2019

Blevins TC, Barve A, Raiter Y, Aubonnet P, Athalye S, Sun B, Muniz R. Efficacy and safety of MYL-1501D versus insulin glargine in patients with type 1 diabetes mellitus: Results of the INSTRIDE 3 phase 3 switch study. Diabetes Obes Metab 2019;21(1):129-35

DT1 Insuline ECRA ✓ ✓ ✓ ✓

Bonifati et al., 2019

Bonifati C, De Felice C, Lora V, Morrone A, Graceffa D. Effectiveness of etanercept biosimilar SB4 in maintaining low disease activity in patients with psoriatic arthritis switched from etanercept originator: An open-label one-year study. J Dermatolog Treat 2019 [Epub ahead of print]

AP Etanercept ENCAA ✓

Bronswijk et al., 2020

Bronswijk M, Moens A, Lenfant M, Tops S, Compernolle G, Van Assche G, et al. Evaluating efficacy, safety, and pharmacokinetics after switching from infliximab originator to biosimilar CT-P13: Experience from a large tertiary referral center. Inflamm Bowel Dis 2019;26(4):628-34


Buer et al., 2017 Buer LC, Moum BA, Cvancarova M, Warren DJ, Medhus AW, Hoivik ML. Switching from Remicade® to Remsima® is well tolerated and feasible: A prospective, open-label study. J Crohns Colitis 2017;11(3):297-304


Cohen et al., 2020

Cohen SB, Radominski SC, Kameda H, Kivitz AJ, Tee M, Cronenberger C, et al. Long-term efficacy, safety, and immunogenicity of the infliximab (IFX) biosimilar, PF-06438179/GP1111, in patients with rheumatoid arthritis after switching from reference IFX or continuing biosimilar therapy: Week 54-78 data from a randomized, double-blind, phase III trial. BioDrugs 2020;34(2):197-207.

PR Infliximab ECRA +

extension ✓

Cohen et al., 2018

Cohen SB, Alonso-Ruiz A, Klimiuk PA, Lee EC, Peter N, Sonderegger I, Assudani D. Similar efficacy, safety and immunogenicity of adalimumab biosimilar BI 695501 and Humira reference product in patients with moderately to severely active rheumatoid arthritis: Results from the phase III randomised VOLTAIRE-RA equivalence study. Ann Rheum Dis 2018;77(6):914-21

PR Adalimumab ECRA ✓ ✓ ✓

Eberl et al., 2017

Eberl A, Huoponen S, Pahikkala T, Blom M, Arkkila P, Sipponen T. Switching maintenance infliximab therapy to biosimilar infliximab in inflammatory bowel disease patients. Scand J Gastroenterol 2017;52(12):1348-53

MC, CU, MIInc Infliximab ENCAA ✓

Emery et al., 2017 Emery P, Vencovsky J, Sylwestrzak A, Leszczynski P, Porawska W, Stasiuk B, et al. Long-term efficacy and safety in patients with

PR Etanercept ECRA +

extension ✓

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rheumatoid arthritis continuing on SB4 or switching from reference etanercept to SB4. Ann Rheum Dis 2017;76:1986-91

Fabiani et al., 2019

Fabiani C, Vitale A, Emmi G, Sgheri A, Lopalco G, Sota J, et al. The role of biosimilars in uveitis: Long-term real-world outcomes of the switch from original to biosimilar TNF-alpha inhibitors. Front Pharmacol 2019;10:1468

Uvéite TNF Inhibiteur Cohorte

rétrospective ✓

Felis-Giemza et al., 2019

Felis-Giemza A, Chmurzynska K, Nalecz-Janik J, Romanowska-Prochnicka K, Swierkocka K, Wudarski M, Olesinska M. Observational study of inflammatory arthritis treatment by etanercept originator switched to an etanercept biosimilar. Reumatologia 2019;57(5):257-63

PR, SA, AP Etanercept ENCAA ✓

Fiorino et al., 2018

Fiorino G, Ruiz-Arguello MB, Maguregui A, Nagore D, Correale C, Radice S, et al. Full interchangeability in regard to immunogenicity between the infliximab reference biologic and biosimilars CT-P13 and SB2 in inflammatory bowel disease. Inflamm Bowel Dis 2018;24(3):601-6


Genovese et al., 2019

Genovese MC, Glover J, Greenwald M, Porawska W, El Khouri EC, Dokoupilova E, et al. FKB327, an adalimumab biosimilar, versus the reference product: Results of a randomized, Phase III, double-blind study, and its open-label extension. Arthritis Res Ther 2019;21(1):281

PR Adalimumab ECRA +

extension ✓ ✓

Gervais et al., 2018

Gervais L, McLean LL, Wilson ML, Cameron C, Curtis L, Garrick V, et al. Switching from originator to biosimilar infliximab in paediatric inflammatory bowel disease is feasible and uneventful. J Pediatr Gastroenterol Nutr 2018;67(6):745-8


Glintborg et al., 2019

Glintborg B, Loft AG, Omerovic E, Hendricks O, Linauskas A, Espesen J, et al. To switch or not to switch: Results of a nationwide guideline of mandatory switching from originator to biosimilar etanercept. One-year treatment outcomes in 2061 patients with inflammatory arthritis from the DANBIO registry. Ann Rheum Dis 2019;78(2):192-200

PR, AP, SA Etanercept Cohorte

rétrospective et historique

✓ ✓

Glintborg et al., 2017

Glintborg B, Sorensen IJ, Loft AG, Lindegaard H, Linauskas A, Hendricks O, et al. A nationwide non-medical switch from originator infliximab to biosimilar CT-P13 in 802 patients with inflammatory arthritis: 1-year clinical outcomes from the DANBIO registry. Ann Rheum Dis 2017;76(8):1426-31

PR, AP, SA Infliximab Cohorte

rétrospective et historique

✓ ✓

Goll et al., 2019

Goll GL, Jorgensen KK, Sexton J, Olsen IC, Bolstad N, Haavardsholm EA, et al. Long-term efficacy and safety of biosimilar infliximab (CT-P13) after switching from originator infliximab: Open-label extension of the NOR-SWITCH trial. J Intern Med 2019;285(6):653-69

PR, AP, SA, Ps, MC, CU

Infliximab ECRA +

extension ✓

Griffiths et al., 2017

Griffiths CE, Thaci D, Gerdes S, Arenberger P, Pulka G, Kingo K, et al. The EGALITY study: A confirmatory, randomized, double-blind study

Ps Etanercept ECRA ✓ ✓ ✓

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comparing the efficacy, safety and immunogenicity of GP2015, a proposed etanercept biosimilar, vs. the originator product in patients with moderate-to-severe chronic plaque-type psoriasis. Br J Dermatol 2017;176(4):928-38

Guerra Veloz et al., 2019

Guerra Veloz MF, Belvis Jimenez M, Valdes Delgado T, Castro Laria L, Maldonado Perez B, Perea Amarillo R, et al. Long-term follow up after switching from original infliximab to an infliximab biosimilar: Real-world data. Therap Adv Gastroenterol 2019;12:1756284819858052


Guerra Veloz et al., 2018a

Guerra Veloz MF, Argüelles-Arias F, Castro Laria L, Maldonado Perez B, Benitez Roldan A, Perea Amarillo R, et al. Loss of efficacy and safety of the switch from infliximab original to infliximab biosimilar (CT-P13) in patients with inflammatory bowel disease. World J Gastroenterol 2018a;24(46):5288-96

MC, CU Infliximab Cohortes

rétrospective et prospective

✓ ✓ ✓

Guerra Veloz et al., 2018b

Guerra Veloz MF, Vazquez Moron JM, Belvis Jimenez M, Pallares Manrique H, Valdes Delgado T, Castro Laria L, et al. Switching from reference infliximab to CT-P13 in patients with inflammatory bowel disease: Results of a multicenter study after 12 months. Rev Esp Enferm Dig 2018b;110(9):564-70


Guerrero Puente et al., 2017

Guerrero Puente L, Iglesias Flores E, Benitez JM, Medina Medina R, Salgueiro Rodriguez I, Aguilar Melero P, et al. Evolution after switching to biosimilar infliximab in inflammatory bowel disease patients in clinical remission. Gastroenterol Hepatol 2017;40(9):595-604


Guiotto et al., 2019

Guiotto C, Italia A, Lavagna A, Rigazio C, Cosimato M, Ercole E, et al. Switching from infliximab originator to a first biosimilar is safe and effective. Results of a case-control study with drug levels and antibodies evaluation. Dig Liver Dis 2019;51(8):1117-22


Haag-Weber et al., 2009

Haag-Weber M, Vetter A, Thyroff-Friesinger U. Therapeutic equivalence, long-term efficacy and safety of HX575 in the treatment of anemia in chronic renal failure patients receiving hemodialysis. Clin Nephrol 2009;72(5):380-90

Anémie Epoetin ECRA +

extension ✓ ✓ ✓

Hadjiyianni et al., 2016

Hadjiyianni I, Dahl D, Lacaya LB, Pollom RK, Chang CL, Ilag LL. Efficacy and safety of LY2963016 insulin glargine in patients with type 1 and type 2 diabetes previously treated with insulin glargine. Diabetes Obes Metab 2016;18(4):425-9

DT1, DT2 Insuline ECRA ✓ ✓ ✓

Hercogova et al., 2020

Hercogova J, Papp KA, Chyrok V, Ullmann M, Vlachos P, Edwards CJ. AURIEL-PsO: A randomized, double-blind phase III equivalence trial to demonstrate the clinical similarity of the proposed biosimilar MSB11022

Ps Adalimumab ECRA ✓ ✓ ✓ ✓

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to reference adalimumab in patients with moderate-to-severe chronic plaque-type psoriasis. Br J Dermatol 2020;182(2):316-26

Hoivik et al., 2018

Hoivik ML, Buer LCT, Cvancarova M, Warren DJ, Bolstad N, Moum BA, Medhus AW. Switching from originator to biosimilar infliximab – Real world data of a prospective 18 months follow-up of a single-centre IBD population. Scand J Gastroenterol 2018;53(6):692-9


Jaworski et al., 2019

Jaworski J, Matucci-Cerinic M, Schulze-Koops H, Buch MH, Kucharz EJ, Allanore Y, et al. Switch from reference etanercept to SDZ ETN, an etanercept biosimilar, does not impact efficacy, safety, and immunogenicity of etanercept in patients with moderate-to-severe rheumatoid arthritis: 48-week results from the phase III, randomized, double-blind EQUIRA study. Arthritis Res Ther 2019;21(1):130

PR Etanercept ECRA +

extension ✓

Jorgensen et al., 2017

Jorgensen KK, Olsen IC, Goll GL, Lorentzen M, Bolstad N, Haavardsholm EA, et al. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): A 52-week, randomised, double-blind, non-inferiority trial. Lancet 2017;389(10086):2304-16

PR, AP, SA, Ps, MC, UC

Infliximab ECRA ✓ ✓ ✓ ✓

Kaltsonoudis et al., 2019

Kaltsonoudis E, Pelechas E, Voulgari PV, Drosos AA. Maintained clinical remission in ankylosing spondylitis patients switched from reference infliximab to its biosimilar: An 18-month comparative open-label study. J Clin Med 2019;8(7):956

SA Infliximab Cohortes

prospectives ✓ ✓ ✓

Kang et al., 2018

Kang B, Lee Y, Lee K, Choi YO, Choe YH. Long-term outcomes after switching to CT-P13 in pediatric-onset inflammatory bowel disease: A single-center prospective observational study. Inflamm Bowel Dis 2018;24(3):607-16


prospectives ✓ ✓ ✓ ✓

Kolar et al., 2017

Kolar M, Duricova D, Bortlik M, Hruba V, Machkova N, Mitrova K, et al. Infliximab biosimilar (RemsimaTM) in therapy of inflammatory bowel diseases patients: Experience from one tertiary inflammatory bowel diseases centre. Dig Dis 2017;35(1-2):91-100


Lukas et al., 2020

Lukas M, Malickova K, Kolar M, Bortlik M, Vasatko M, Machkova N, et al. Switching from originator adalimumab to the biosimilar SB5 in patients with inflammatory bowel disease: Short-term experience from a single tertiary clinical center. J Crohns Colitis 2020 [Epub ahead of print]

MC, CU, MIInc Adalimumab Cohortes

rétrospectives ✓ ✓

Matsuno et Matsubara, 2019

Matsuno H et Matsubara T. A randomized double-blind parallel-group phase III study to compare the efficacy and safety of NI-071 and infliximab reference product in Japanese patients with active rheumatoid arthritis refractory to methotrexate. Mod Rheumatol 2019;29(6):919-27


extension ✓

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Minutolo et al., 2017

Minutolo R, Bolasco P, Chiodini P, Sposini S, Borzumati M, Abaterusso C, et al. Effectiveness of switch to erythropoiesis-stimulating agent (ESA) biosimilars versus maintenance of ESA originators in the real-life setting: Matched-control study in hemodialysis patients. Clin Drug Investig 2017;37(10):965-73

Anémie Epoetin Cohortes

rétrospectives ✓

Nikiphorou et al., 2015

Nikiphorou E, Kautiainen H, Hannonen P, Asikainen J, Kokko A, Rannio T, Sokka T. Clinical effectiveness of CT-P13 (Infliximab biosimilar) used as a switch from Remicade (infliximab) in patients with established rheumatic disease. Report of clinical experience based on prospective observational data. Expert Opin Biol Ther 2015;15(12):1677-83

PR, AP, SA Infliximab ENCAA ✓

Papp et al., 2017

Papp K, Bachelez H, Costanzo A, Foley P, Gooderham M, Kaur P, et al. Clinical similarity of biosimilar ABP 501 to adalimumab in the treatment of patients with moderate to severe plaque psoriasis: A randomized, double-blind, multicenter, phase III study. J Am Acad Dermatol 2017;76(6):1093-102

Ps Adalimumab ECRA ✓ ✓ ✓ ✓

Park et al., 2017a

Park W, Suh CH, Shim SC, Molina FFC, Jeka S, Medina-Rodriguez FG, et al. Efficacy and safety of switching from innovator rituximab to biosimilar CT-P10 compared with continued treatment with CT-P10: Results of a 56-week open-label study in patients with rheumatoid arthritis. BioDrugs 2017a;31(4):369-77

PR Rituximab ECRA +

extension ✓

Park et al., 2017b

Park W, Yoo DH, Miranda P, Brzosko M, Wiland P, Gutierrez-Ureña S, et al. Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study. Ann Rheum Dis 2017b;76(2):346-54


extension ✓

Pescitelli et al., 2019

Pescitelli L, Lazzeri L, Di Cesare A, Tripo L, Ricceri F, Prignano F. Clinical experience with the etanercept biosimilar SB4 in psoriatic patients. Int J Clin Pharm 2019;41(1):9-12

PR, Ps Etanercept ENCAA ✓

Petitdidier et al., 2019

Petitdidier N, Tannoury J, de'Angelis N, Gagniere C, Hulin A, Rotkopf H, et al. Patients' perspectives after switching from infliximab to biosimilar CT-P13 in patients with inflammatory bowel disease: A 12-month prospective cohort study. Dig Liver Dis 2019;51(12):1652-60


Plevris et al., 2019

Plevris N, Jones GR, Jenkinson PW, Lyons M, Chuah CS, Merchant LM, et al. Implementation of CT-P13 via a managed switch programme in Crohn's disease: 12-month real-world outcomes. Dig Dis Sci 2019;64(6):1660-7


Ratnakumaran et al., 2018

Ratnakumaran R, To N, Gracie DJ, Selinger CP, O'Connor A, Clark T, et al. Efficacy and tolerability of initiating, or switching to, infliximab


prospectives ✓ ✓

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biosimilar CT-P13 in inflammatory bowel disease (IBD): A large single-centre experience. Scand J Gastroenterol 2018;53(6):700-7

Razanskaite et al., 2017

Razanskaite V, Bettey M, Downey L, Wright J, Callaghan J, Rush M, et al. Biosimilar infliximab in inflammatory bowel disease: Outcomes of a managed switching programme. J Crohns Colitis 2017;11(6):690-6


Rosenstock et al., 2015

Rosenstock J, Hollander P, Bhargava A, Ilag LL, Pollom RK, Zielonka JS, et al. Similar efficacy and safety of LY2963016 insulin glargine and insulin glargine (Lantus®) in patients with type 2 diabetes who were insulin-naive or previously treated with insulin glargine: A randomized, double-blind controlled trial (the ELEMENT 2 study). Diabetes Obes Metab 2015;17(8):734-41

DT2 Insuline ECRA ✓

Scherlinger et al., 2018

Scherlinger M, Germain V, Labadie C, Barnetche T, Truchetet ME, Bannwarth B, et al. Switching from originator infliximab to biosimilar CT-P13 in real-life: The weight of patient acceptance. Joint Bone Spine 2018;85(5):561-7

PR, SA Infliximab Cohortes

prospective et rétrospective

✓

Schmitz et al., 2017

Schmitz EM, Benoy-De Keuster S, Meier AJ, Scharnhorst V, Traksel RA, Broeren MA, Derijks LJ. Therapeutic drug monitoring (TDM) as a tool in the switch from infliximab innovator to biosimilar in rheumatic patients: Results of a 12-month observational prospective cohort study. Clin Rheumatol 2017;36(9):2129-34

PR, AP, SA, PR+CU, Periferal

arthritis+CU

Infliximab ENCAA ✓

Schmitz et al., 2018

Schmitz EM, Boekema PJ, Straathof JW, van Renswouw DC, Brunsveld L, Scharnhorst V, et al. Switching from infliximab innovator to biosimilar in patients with inflammatory bowel disease: A 12-month multicentre observational prospective cohort study. Aliment Pharmacol Ther 2018;47(3):356-63


Shim et al., 2019

Shim SC, Bozic-Majstorovic L, Berrocal Kasay A, El-Khouri EC, Irazoque-Palazuelos F, Cons Molina FF, et al. Efficacy and safety of switching from rituximab to biosimilar CT-P10 in rheumatoid arthritis: 72-week data from a randomized Phase 3 trial. Rheumatology (Oxford) 2019;58(12):2193-202

PR Rituximab ECRA ✓ ✓ ✓ ✓

Sieczkowska et al., 2016

Sieczkowska J, Jarzebicka D, Banaszkiewicz A, Plocek A, Gawronska A, Toporowska-Kowalska E, et al. Switching between infliximab originator and biosimilar in paediatric patients with inflammatory bowel disease. Preliminary observations. J Crohns Colitis 2016;10(2):127-32


Smits et al., 2019 Smits LJ, van Esch AA, Derikx LA, Boshuizen R, de Jong DJ, Drenth JP, Hoentjen F. Drug survival and immunogenicity after switching from Remicade to biosimilar CT-P13 in inflammatory bowel disease patients:


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Two-year follow-up of a prospective observational cohort study. Inflamm Bowel Dis 2019;25(1):172-9

Smits et al., 2017

Smits LJ, Grelack A, Derikx LA, de Jong DJ, van Esch AA, Boshuizen RS, et al. Long-term clinical outcomes after switching from Remicade® to biosimilar CT-P13 in inflammatory bowel disease. Dig Dis Sci 2017;62(11):3117-22


Smits et al., 2016

Smits LJ, Derikx LA, de Jong DJ, Boshuizen RS, van Esch AA, Drenth JP, Hoentjen F. Clinical outcomes following a switch from Remicade® to the biosimilar CT-P13 in inflammatory bowel disease patients: A prospective observational cohort study. J Crohns Colitis 2016;10(11):1287-93


Smolen et al., 2018

Smolen JS, Choe JY, Prodanovic N, Niebrzydowski J, Staykov I, Dokoupilova E, et al. Safety, immunogenicity and efficacy after switching from reference infliximab to biosimilar SB2 compared with continuing reference infliximab and SB2 in patients with rheumatoid arthritis: Results of a randomised, double-blind, phase III transition study. Ann Rheum Dis 2018;77(2):234-40

PR Infliximab ECRA ✓ ✓ ✓ ✓

Strik et al., 2018

Strik AS, van de Vrie W, Bloemsaat-Minekus JP, Nurmohamed M, Bossuyt PJ, Bodelier A, et al. Serum concentrations after switching from originator infliximab to the biosimilar CT-P13 in patients with quiescent inflammatory bowel disease (SECURE): An open-label, multicentre, phase 4 non-inferiority trial. Lancet Gastroenterol Hepatol 2018;3(6):404-12

MC, CU Infliximab ECRA ✓

Tanaka et al., 2017

Tanaka Y, Yamanaka H, Takeuchi T, Inoue M, Saito K, Saeki Y, et al. Safety and efficacy of CT-P13 in Japanese patients with rheumatoid arthritis in an extension phase or after switching from infliximab. Mod Rheumatol 2017;27(2):237-45


extension ✓

Thadhani et al., 2018

Thadhani R, Guilatco R, Hymes J, Maddux FW, Ahuja A. Switching from epoetin alfa (Epogen®) to epoetin alfa-epbx (RetacritTM) using a specified dosing algorithm: A randomized, non-inferiority study in adults on hemodialysis. Am J Nephrol 2018;48(3):214-24

Anémie Epoetin ECRA ✓ ✓ ✓

Tony et al., 2019

Tony HP, Krüger K, Cohen SB, Schulze-Koops H, Kivitz AJ, Jeka S, et al. Brief report: Safety and immunogenicity of rituximab biosimilar GP 2013 after switch from reference rituximab in patients with active rheumatoid arthritis. Arthritis Care Res (Hoboken) 2019;71(1):88-94

PR Rituximab ECRA ✓ ✓

Tweehuysen et al., 2018a

Tweehuysen L, Huiskes VJ, van den Bemt BJ, Vriezekolk JE, Teerenstra S, van den Hoogen FHJ, et al. Open-label, non-mandatory transitioning PR, AP, SA Etanercept

Cohortes prospective et

historique ✓ ✓ ✓

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from originator etanercept to biosimilar SB4: Six-month results from a controlled cohort study. Arthritis Rheumatol 2018a;70(9):1408-18

Tweehuysen et al., 2018b

Tweehuysen L, van den Bemt BJ, van Ingen IL, de Jong AJ, van der Laan WH, van den Hoogen FH, den Broeder AA. Subjective complaints as the main reason for biosimilar discontinuation after open-label transition from reference infliximab to biosimilar infliximab. Arthritis Rheumatol 2018b;70(1):60-8

PR, AP, SA Infliximab Cohorte

prospective ✓

Van Hoeve et al., 2019

Van Hoeve K, Dreesen E, Hoffman I, Van Assche G, Ferrante M, Gils A, Vermeire S. Efficacy, Efficacy, pharmacokinetics and immunogenicity is not affected by switching from infliximab originator to a biosimilar in pediatric patients with inflammatory bowel disease. Ther Drug Monit 2019;41(3):317-24


rétrospective et prospective

✓ ✓

Vergara-Dangond et al., 2017

Vergara-Dangond C, Saez Bello M, Climente Marti M, Llopis Salvia P, Alegre-Sancho JJ. Effectiveness and safety of switching from innovator infliximab to biosimilar CT-P13 in inflammatory rheumatic diseases: A real-world case study. Drugs R D 2017;17(3):481-5

PR, AP, SA Infliximab Cohortes

prospectives ✓ ✓ ✓

Von Minckwitz et al., 2018

Von Minckwitz G, Colleoni M, Kolberg HC, Morales S, Santi P, Tomasevic Z, et al. Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): A randomised, double-blind, phase 3 trial. Lancet Oncol 2018;19(7):987-98

Cancer sein Trastuzumab ECRA ✓ ✓

Weinblatt et al., 2018

Weinblatt ME, Baranauskaite A, Dokoupilova E, Zielinska A, Jaworski J, Racewicz A, et al. Switching from reference adalimumab to SB5 (adalimumab biosimilar) in patients with rheumatoid arthritis: Fifty-two-week phase III randomized study results. Arthritis Rheumatol 2018;70(6):832-40

PR Adalimumab ECRA ✓ ✓ ✓ ✓

Yamanaka et al., 2020

Yamanaka H, Kamatani N, Tanaka Y, Hibino T, Drescher E, Sanchez-Burson J, et al. A comparative study to assess the efficacy, safety, and immunogenicity of YLB113 and the etanercept reference product for the treatment of patients with rheumatoid arthritis. Rheumatol Ther 2020;7(1):149-63

PR Adalimumab ECRA +

extension ✓ ✓

Yazici et al., 2018

Yazici Y, Xie L, Ogbomo A, Ellis LA, Goyal K, Teeple A, Simsek I. Analysis of real-world treatment patterns in a matched rheumatology population that continued innovator infliximab therapy or switched to biosimilar infliximab. Biologics 2018;12:127-34

PR Infliximab Cohortes

rétrospectives ✓

Ye et al., 2019 Ye BD, Pesegova M, Alexeeva O, Osipenko M, Lahat A, Dorofeyev A, et al. Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: An international,

MC Infliximab ECRA ✓ ✓ ✓ ✓

15


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randomised, double-blind, phase 3 non-inferiority study. Lancet 2019;393(10182):1699-707.

Yoo et al., 2017

Yoo DH, Prodanovic N, Jaworski J, Miranda P, Ramiterre E, Lanzon A, et al. Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: Comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study. Ann Rheum Dis 2017;76(2):355-63


extension ✓

Guide de pratique clinique (GPC)

Araujo et al., 2017 Araujo FC, Sepriano A, Teixeira F, Jesus D, Rocha TM, Martins P, et al. The Portuguese Society of Rheumatology position paper on the use of biosimilars – 2017 update. Acta Reumatol Port 2017;42(3):219-28

GPC ✓

Kay et al., 2018 Kay J, Schoels MM, Dorner T, Emery P, Kvien TK, Smolen JS, et al. Consensus-based recommendations for the use of biosimilars to treat rheumatological diseases. Ann Rheum Dis 2018;77(2):165-74

GPC ✓

Ward et al., 2019

2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network recommendations for the treatment of ankylosing spondylitis and nonradiographic axial spondyloarthritis. Arthritis Rheumatol 2019;71(10):1599-613

GPC ✓

Xibille et al., 2018 Xibille D, Carrillo S, Huerta-Sil G, Hernandez R, Limon L, Olvera-Soto G, et al. Current state of biosimilars in Mexico: The position of the Mexican College of Rheumatology, 2016. Reumatol Clin 2018;14(3):127-36

GPC ✓

Énoncé de position

AAD, 2013 American Academy of Dermatology (AAD). Position statement on generic therapeutic and biosimilar substitution. Rosemont, IL : AAD; 2013. Disponible à : https://server.aad.org/forms/policies/uploads/ps/ps-generic%20therapeutic%20and%20%20biosimilar%20substitution.pdf.

ACD, 2013 Association canadienne de dermatologie (ACD). Énoncé de principe de l'Association canadienne de dermatologie : les biosimilaires. Ottawa, ON : ACD; 2013. Disponible à : https://dermatology.ca/wp-content/uploads/2013/09/Biosimilars-WEB-FR-2013.pdf.

ACR, 2018 American College of Rheumatology (ACR). Position statement: Biosimilars. Atlanta, GA : ACR; 2018. Disponible à : https://www.rheumatology.org/Portals/0/Files/Biosimilars-Position-Statement.pdf?ver=2018-05-21-134110-000.

Azevedo et al., 2015

Azevedo VF, Meirelles Ede S, Kochen Jde A, Medeiros AC, Miszputen SJ, Teixeira FV, et al. Recommendations on the use of biosimilars by the Brazilian Society of Rheumatology, Brazilian Society of Dermatology, Brazilian Federation of Gastroenterology and Brazilian Study Group on Inflammatory Bowel Disease—Focus on clinical evaluation of monoclonal antibodies and fusion proteins used in the treatment of autoimmune diseases. Autoimmun Rev 2015;14(9):769-73.

Baumgärtel, 2017 Baumgärtel C. Austrian medicines authority positive towards biosimilar interchangeability. Generics and Biosimilars Initiative Journal 2017;6(1):41.

Biosimilar Medicines, 2019

Biosimilar Medicines. Positioning statements on physician-led switching for biosimilar medicines. Bruxelles, Belgique : Medicines for Europe; 2019. Disponible à : https://www.medicinesforeurope.com/wp-content/uploads/2017/03/M-Biosimilars-Overview-of-positions-on-physician-led-switching.pdf.

Diabetes Canada, 2019

Diabetes Canada. Diabetes, biologic drugs, and biosimilar insulins [site Web]. Toronto, ON : Diabetes Canada; 2019. Disponible à : https://www.diabetes.ca/advocacy---policies/our-policy-positions/diabetes,-biologic-drugs,-and-biosimilar-insulins (consulté le 23 janvier 2020).

16


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Danese et al., 2017

Danese S, Fiorino G, Raine T, Ferrante M, Kemp K, Kierkus J, et al. ECCO position statement on the use of biosimilars for inflammatory bowel disease—An update. J Crohns Colitis 2017;11(1):26-34.

De Ridder et al., 2019

De Ridder L, Assa A, Bronsky J, Romano C, Russell RK, Afzal NA, et al. Use of biosimilars in pediatric inflammatory bowel disease: An updated position statement of the Pediatric IBD Porto Group of ESPGHAN. J Pediatr Gastroenterol Nutr 2019;68(1):144-53.

EMA, 2017 European Medicines Agency (EMA). Guideline on immunogenicity assessment of therapeutic proteins. Londres, Angleterre : EMA; 2017. Disponible à : https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-immunogenicity-assessment-therapeutic-proteins-revision-1_en.pdf.

FDA, 2017 Food and Drug Administration (FDA). Prescribing biosimilar products. Silver Spring, MD : FDA; 2017. Disponible à : https://www.fda.gov/media/108103/download.

Fernandes et al., 2018

Fernandes GS, Sternberg C, Lopes G, Chammas R, Gifoni MAC, Gil RA, Araujo DV. T The use of biosimilar medicines in oncology – Position statement of the Brazilian Society of Clinical Oncology (SBOC). Braz J Med Biol Res 2018;51(3):e7214.

Fiorino et al., 2018

Fiorino G, Caprioli F, Daperno M, Mocciaro F, Principi M, Viscido A, et al. Use of biosimilars in inflammatory bowel disease: A position update of the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD). Dig Liver Dis 2019;51(5):632-9.

Fonseca et al., 2017

Fonseca VA, Bloomgarden ZT, Dagogo-Jack S, Grunberger G, Einhorn D, Garber AJ, et al. AACE/ACE position statement on the use of follow-on biologics and biosimilars for endocrine diseases. Endocr Pract 2017;23(11):1345-9.

Franchimont et al., 2018

Franchimont D, Ferrante M, Louis E, De Vos M, Dewit O, Van Hootegem P, et al. Belgian IBD research group (BIRD) position statement 2017 on the use of biosimilars in inflammatory bowel diseases (IBD). Acta Gastroenterol Belg 2018;81(1):49-53.

Halabi et al., 2018 Halabi H, Zahrani ZA, Swailem RA, Husain W, Rayes HA, Osaimi HA, et al. Biosimilars in rheumatic diseases: Regulatory guidelines, efficacy and safety implications in Saudi Arabia. Open Rheumatol J 2018;12(1):313-22.

HAS, 2017 Haute Autorité de Santé (HAS). Bon usage du médicament – Les médicaments biosimilaires. Saint-Denis La Plaine, France : HAS; 2017. Disponible à : https://www.has-sante.fr/upload/docs/application/pdf/2017-11/bum_medicaments_biosimilaires_v1.pdf.

HIS, 2018 Healthcare Improvement Scotland (HIS). Biosimilar medicines: A national prescribing framework. Édimbourg, Écosse : HIS; 2018. Disponible à : http://www.healthcareimprovementscotland.org/our_work/technologies_and_medicines/programme_resources/biosimilar_medicines_framework.aspx.

Ho et al., 2019 Ho CT, Mok CC, Cheung TT, Kwok KY, Yip RM. Management of rheumatoid arthritis: 2019 updated consensus recommendations from the Hong Kong Society of Rheumatology. Clin Rheumatol 2019;38(12):3331-50.

ISOPP, 2019 International Society of Oncology Pharmacy Practioners (ISOPP). ISOPP global position on the use of biosimilars in cancer treatment and supportive care. Vancouver, BC : ISOPP; 2019. Disponible à : https://www.isopp.org/sites/default/files/resource/files/ISOPP%20Global%20Position%20on%20the%20Use%20of%20Biosimilars.pdf.

Jahnz-Rozyk et al., 2019

Jahnz-Rozyk K, Brzosko M, Lech-Maranda E, Narbutt J, Owczarek W, Rekas M, et al. The Polish Expert Group position statement on the safety of biological treatments with monoclonal antibodies and fusion proteins: An update. Journal of Health Policy and Outcomes Research 2019;(1):10-6.

Lyman et al., 2018

Lyman GH, Balaban E, Diaz M, Ferris A, Tsao A, Voest E, et al. American Society of Clinical Oncology statement: Biosimilars in oncology. J Clin Oncol 2018;36(12):1260-5

Martinez-Lopez de Castro et al., 2018

Martinez-Lopez de Castro N, Matilla-Fernandez MB, Fraga-Fuentes MD, Mangues-Bafalluy I, Asensi-Diez R, G. C-O. Spanish Society of Hospital Pharmacy position paper on biosimilar medicines. Farm Hosp 2018;42(4):180-3.

Moayyedi et al., 2020

Moayyedi P, Benchimol EI, Armstrong D, Yuan C, Fernandes A, Leontiadis GI. Joint Canadian Association of Gastroenterology and Crohn's Colitis Canada position statement on biosimilars for the treatment of inflammatory bowel disease. J Can Assoc Gastroenterol 2020;3(1):e1-e9.

Mularczyk et al., 2014

Mularczyk A, Gonciarz M, Bartnik W, Durlik M, Eder P, Gasiorowska A, et al. Biosimilar medicines – Their use in the treatment of inflammatory bowel diseases. Position statement of the Working Group of the Polish National Consultant in Gastroenterology. Prz Gastroenterol 2014;9(1):1-3.

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Nakashima, 2019 Nakashima L. III-190 Oncology biosimilars utilization policy. Vancouver, BC : BC Cancer, Provincial Health Services Authority; 2019. Disponible à : http://shop.healthcarebc.ca/phsa/BCCancer/Systemic%20Therapy/70329.pdf.

NICE, 2016 National Institute for Health and Care Excellence (NICE). Biosimilar medicines. Londres, Angleterre : NICE; 2016. Disponible à : https://www.nice.org.uk/advice/ktt15/resources/biosimilar-medicines-pdf-58757954414533.

NRAS, 2019 National Rheumatoid Arthritis Society (NRAS). NRAS position paper on biosimilar medicines – Updated February, 2019. Maidenhead, Royaume-Uni : NRAS; 2019. Disponible à : https://www.nras.org.uk/data/files/About%20RA/How%20is%20RA%20managed/NRAS%20revised%20position%20paper%20biosimilars%20Feb%202019.pdf.

Roediger et al., 2017

Roediger A, Freischem B, Reiland J-P. What pricing and reimbursement policies to use for off-patent biologicals in Europe? – Results from the second EBE

biological medicines policy survey. Generics and Biosimilars Initiative Journal 2017;6(2):61-78.

SAMAC, 2017

South Australia Medicines Advisory Committee (SAMAC). Biosimilars - Guiding principles for the governance of biological and biosimilar medicines. Adelaïde, Australie : SA Health; 2017. Disponible à : https://www.sahealth.sa.gov.au/wps/wcm/connect/02994280419bed2e8251badb31a1ff3d/Biosimilars_Guiding+principles+for+the+governance+of+biological+and+biosimilar+medicines.pdf.

SCR, 2019 Société canadienne de rhumatologie (SCR). Énoncé de position de la Société canadienne de rhumatologie sur les biosimilaires [site Web]. Mississauga, ON : SCR; 2019. Disponible à : https://rheum.ca/fr/enonce-de-position-de-la-societe-canadienne-de-rhumatologie-sur-les-biosimilaires/ (consulté le 23 janvier 2020)

Tabernero et al., 2016

Tabernero J, Vyas M, Giuliani R, Arnold D, Cardoso F, Casali PG, et al. Biosimilars: A position paper of the European Society for Medical Oncology, with particular reference to oncology prescribers. ESMO Open 2016;1(6):e000142.

Wiek, 2018 Wiek D. Biosimilars – Position Paper: Updating position statement from the European League Against Rheumatism (EULAR) Standing Committee of People with Arthritis/Rheumatism in Europe (PARE). Zurich, Suisse : EULAR PARE; 2018. Disponible à : https://www.eular.org/myUploadData/files/biosimilars_paper_updated_2018_09_14_dw.pdf.

18

ANNEXE C

Évaluation de la qualité méthodologique des documents

Tableau C1 – Évaluation des études primaires : Grille ASPC

Auteurs (Année)

Abdalla (2017)

Alten (2019)

Argüelles-Arias (2017)

Avouac (2018)

Belleudi (2019)

Benucci (2017)

Bergqvist (2018)

Blackwell (2018)

Blauvelt (2018)

Plan d’étude ENCAA ECRA ENCAA ENCAA Cohorte

rétrospective ENCAA ENCAA ECRA ECRA

Évaluateurs #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2

2. Participants de l’étude représentatifs de la population cible

M M F F M M M M F F M F F F F F F F

3. Justesse du contrôle du biais de sélection

Fa Fa F F M Fa M M M M Fa Fa M M F F F F

4. Justesse du contrôle du biais causé par une erreur de classification

Fa M F F M M F F M Fa Fa M M M F F F F

5. Justesse du contrôle du biais d’information

Fa Fa F F M Fa M Fa M M Fa Fa M Fa F F F F

6. Validité et fiabilité des instruments de collecte de données

M M F F F M F M F F M F F F F F M F

7. Justesse de la conservation et du suivi F F M M M F M F F F F F M F M M F M

8. Comparabilité du groupe témoin et du groupe d’intervention

Fa Fa F F Fa Fa M Fa M M Fa Fa M M F F F F

9. Justesse du contrôle des grandes variables confusionnelles

Fa Fa M F Fa Fa F Fa M Fa Fa Fa M Fa M F F F

10. Justesse de la conduite éthique Fa Fa F F F F F F F F F F F F F F F F

11. Justesse et interprétation des tests statistiques

Fa M M Fa M Fa F F F M M M M M M M F F

12. Puissance et taille de l’échantillon F F F M F F F F F F Fa Fa M F F M F F

Qualité de l’étude Fa Fa Mo Mo Mo Mo Mo Mo Mo Mo Fa Fa Mo Mo M M E E

Évaluation de la qualité méthodologique

Faible Moyenne Moyenne Moyenne Moyenne Faible Moyenne Moyenne Élevée

19

Tableau C1 – Évaluation des études primaire : Grille ASPC (suite 1)

Auteurs (Année)

Blevins (2019)

Bonifati (2019)

Buer (2017)

Bronswijk (2020)

Cohen (2020)

Cohen (2018)

Eberl (2017)

Emery (2017)

Fabiani (2019)

Felis-Giemza (2019)

Fiorino (2018)

Plan d’étude ECRA ENCAA ENCAA ENCAA ECRA ECAA ENCAA ENCAA ENCAA ENCAA ENCAA

Évaluateurs #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2


F F M M M M M M F F F F M M F F M M M M M M


F F Fa M M Fa Fa Fa M M F F M M M M M Fa Fa Fa Fa Fa


F F M F M Fa M Fa F F M F Fa Fa M M M Fa M M Fa Fa


M M M Fa M Fa M M M M F F M Fa M F M M M Fa M M


F F M F F M M M M F M F F F F F M M M M F F

7. Justesse de la conservation et du suivi F F F M F F F F F Fa F F Fa F F F F F M M F F


F M Fa Fa M Fa Fa Fa Fa Fa F F M Fa Fa F Fa Fa Fa Fa Fa Fa


M F Fa Fa M Fa Fa Fa Fa Fa F F M Fa Fa Fa Fa Fa Fa Fa Fa Fa

10. Justesse de la conduite éthique F F F Fa F Fa Fa F F F F F F F F F F F -- F F F


M M M F M M Fa Fa M M M M M M M Fa M M Fa Fa M M

12. Puissance et taille de l’échantillon M F Fa F M M Fa Fa M M F M M Fa F Fa M M M M M M

Qualité de l’étude Mo Mo Mo Mo Mo Mo Fa Fa Mo Mo Mo Mo Fa Fa Mo Mo Mo Mo Fa Fa Fa Fa

Évaluation de la qualité méthodologique Moyenne Moyenne Moyenne Faible Moyenne Moyenne Faible Moyenne Moyenne Faible Faible

20


Auteurs (Année)

Gervais (2018)

Genovese (2019)

Glintborg (2017)

Glintborg (2019)

Goll (2019)

Griffiths (2017)

Guerra Veloz REED (2018)

Guerra Veloz WJG

(2018)

Guerra Veloz (2019)

Guerrero Puente (2017)

Guiotto (2019)

Plan d’étude ENCAA ECRA

Cohorte rétrospect

ive et historique

Cohorte rétrospect

ive et historique

ENCAA ECRA ENCAA Cohorte

prospective et rétrospective

ENCAA ENCAA ENCAA

Évaluateurs #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2


M F F F F F F F F F F F F F M M M M M M M M


M M F F M Fa M M M M F F M M M Fa M M Fa M Fa M


M Fa F F M M M M F M F F F Fa F M F M Fa M Fa M


M Fa M M Fa M Fa M F M F F M Fa M M M Fa M Fa M Fa


M F M F M M M F F F M F F F F M F F F F F M

7. Justesse de la conservation et du suivi M F M M M M M M M F F F M M F F Fa F F F Fa Fa


M Fa F F Fa Fa Fa M M M F F M Fa F M M Fa Fa Fa Fa Fa


Fa Fa F F Fa M Fa Fa Fa M M M M Fa M Fa Fa Fa M Fa M M

10. Justesse de la conduite éthique Fa Fa F F - - F Fa F F F F F F F F F F F F Fa F


Fa Fa M M M F M M M M M M M M F M M M F F F M

12. Puissance et taille de l’échantillon M Fa M M F F F M M Fa F M M F M M F F F F F F

Qualité de l’étude Fa Fa Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo

Évaluation de la qualité méthodologique Faible Moyenne Moyenne Moyenne Moyenne Moyenne Moyenne Moyenne Moyenne Moyenne Moyenne

21


Auteurs (Année)

Haag-Weber (2009)

Hercogova (2020)

Hoivik (2018)

Jaworski (2019)

Jorgensen (2017)

Kaltsonoudis (2019)

Kang (2018)

Kolar (2017)

Lukas (2020)

Plan d’étude ECRA ECRA ENCAA ENCAA ECRA Cohorte

prospective Cohorte

prospective ENCAA

Cohorte rétrospective

Évaluateurs #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2


F F F F M M F F F F M M M M M M M M


F F F F M M Fa F F F M M M M Fa M M Fa


F F F F F M F M F F M M F M M M Fa M


F F F F M Fa M F F F Fa M M M M Fa M M


F F M F F F F F F M Fa M F M F F M M

7. Justesse de la conservation et du suivi

F F M F F F F F M F F M M F F F F F


F F F M Fa Fa Fa M F F M F F F Fa M M M


F F F F Fa Fa F F M M Fa F M M Fa M Fa Fa

10. Justesse de la conduite éthique

Fa F F Fa F Fa F F F F F F F F Fa Fa F F


M M M M F M M F F M M F F M M M M M

12. Puissance et taille de l’échantillon

F F F M M F F Fa F F M M F M F F M M

Qualité de l’étude E E Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo


Élevée Moyenne Moyenne Moyenne Moyenne Moyenne Moyenne Moyenne Moyenne

22


Auteurs (Année)

Matsuno (2019)

Minutolo (2017)

Nikiphorou (2015)

Papp (2017)

Park – ARD (2017)

Park – BD (2017)

Pescitelli (2019)

Petitdidier (2019)

Plevris (2019)

Plan d’étude ENCAA Cohorte

rétrospective ENCAA ECRA ENCAA ENCAA ENCAA ENCAA ENCAA

Évaluateurs #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2


F M F F M M F F F F F F M M M M M Fa


Fa F M M M M F F F M Fa F Fa M M Fa Fa Fa


F F M M M Fa F M M F M M M M M M M M


M F M M Fa Fa F F M M M M M Fa M M M M


F F F M M Fa M F M F F F M M M M F M


F M M F Fa Fa F M F M M F M F F F M M


Fa M M F M Fa F M F M Fa M Fa Fa Fa Fa Fa Fa


Fa F Fa Fa Fa Fa F F F F Fa Fa Fa Fa Fa Fa Fa Fa

10. Justesse de la conduite éthique F Fa F F F Fa F F F F F F F Fa Fa F F F


M M F M M Fa M F M F Fa Fa M M M M M M

12. Puissance et taille de l’échantillon F F M F Fa Fa F M M M Fa Fa M F M M M M

Qualité de l’étude Mo Mo Mo Mo Fa Fa Mo Mo Mo Mo Fa Fa Mo Mo Mo Mo Mo Mo


Moyenne Moyenne Faible Moyenne Moyenne Faible Moyenne Moyenne Moyenne

23


Auteurs (Année)

Ratnakumaran (2018)

Razanskaite (2017)

Rosenstock (2015)

Scherlinger (2018)

Schmitz (2017)

Schmitz (2018)

Shim (2019)

Sieczkowska (2016)

Smits (2016)

Plan d’étude Cohorte

prospective ENCAA ECRA

Cohorte prospective

ENCAA ENCAA ECRA ENCAA ENCAA

Évaluateurs #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2


M M M M F F M M M M F M F F M M M M


Fa Fa Fa M F F M M Fa Fa M M F F Fa Fa M M


F M M M M M M M M M M M M M Fa M M M


M M M M F F Fa M Fa M M M F F M M M M


F M F F M F M M M F F M F F F F F M


F F Fa F F M F M M Fa Fa Fa F F Fa M F F


Fa M Fa Fa F F M M Fa Fa Fa Fa F F Fa Fa Fa Fa


Fa Fa Fa Fa M F Fa Fa Fa Fa Fa Fa F F Fa Fa Fa Fa

10. Justesse de la conduite éthique Fa Fa Fa Fa F Fa F Fa F Fa Fa Fa Fa F Fa Fa - F


M M M M M F M F M M F M M M M M M M

12. Puissance et taille de l’échantillon M Fa M M F F M F Fa M M F F M M Fa M Fa

Qualité de l’étude Fa Fa Mo Mo Mo Mo Mo Mo Fa Fa Mo Mo Mo Mo Fa Fa Mo Mo


Faible Moyenne Moyenne Moyenne Faible Moyenne Moyenne Faible Moyenne

24


Auteurs (Année)

Smits (2017)

Smits (2019)

Smolen (2018)

Strik (2018)

Tanaka (2017)

Thadhani (2018)

Tony (2019)

Tweehuysen a (2018)

Tweehuysen b (2018)

Van Hoeve (2019)

Vergara-Dangond

(2017)

Plan d’étude ENCAA ENCAA ECRA ENCAA ECRA ECRA ECRA Cohorte

prospective et historique

Cohorte prospective

ENCAA Cohorte

prospective

Évaluateurs #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2


M M M M F F F F F F F F F F M M M F M M M M


M M M M F F M M M M F F F F Fa M Fa M Fa Fa Fa Fa


M M M M F F F M M M F M F M M F M M M M Fa Fa


M M M M F F M M M M M M F F M M Fa M M M M M


F M F M F F F F M M F F F F M F M M F M M M

7. Justesse de la conservation et du suivi M M Fa Fa F F Fa F Fa Fa Fa Fa F F F F F Fa F F F F


Fa Fa Fa Fa F F Fa Fa Fa Fa M F F F M F M Fa Fa M Fa Fa


Fa Fa Fa Fa M F M Fa Fa Fa F F M F Fa M Fa Fa Fa Fa Fa Fa

10. Justesse de la conduite éthique - F - F F F F F F F F F Fa F F - F F F F F Fa


M M M M M Fa F M M M F F M M F F F M F M M Fa

12. Puissance et taille de l’échantillon M Fa M Fa F M F M M Fa F F F M F F F M F M Fa Fa

Qualité de l’étude Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Mo Fa Fa

Évaluation de la qualité méthodologique Moyenne Moyenne Moyenne Moyenne Moyenne Moyenne Moyenne Moyenne Moyenne Moyenne Faible

25


Auteurs (Année)

Von Minckwitz

(2018)

Weinblatt (2018)

Yamanaka (2020)

Yazici (2018)

Ye (2019)

Yoo (2017)

Plan d’étude ECRA ECRA ECRA Cohorte

rétrospective ECRA ENCAA

Évaluateurs #1 #2 #1 #2 #1 #2 #1 #2 #1 #2 #1 #2


F F F F F F M M F F F F


F F F F F F M M F F Fa M


F M F F F F M M F F M M


F F F F M M Fa Fa F F M M


F M F F M F M M F F F M


M F F F M F Fa Fa F F F M


F F F F F F M M F F Fa M


F F F F M F Fa Fa F F Fa Fa

10. Justesse de la conduite éthique F F F F F F - - F F F F


M M M M M M M M F M M M

12. Puissance et taille de l’échantillon M F M M M M F M F F F F

Qualité de l’étude Mo Mo Mo Mo Mo Mo Fa Fa E E Mo Mo


Moyenne Moyenne Moyenne Faible Élevé Moyenne

26

Tableau C2 – Évaluation des guides de pratique clinique retenus (AGREE-GRS)

AGREE GLOBAL RATING SCALE Araujo 2017

Kay 2018

Ward 2019

Xibille 2018

1. Rate the overall quality of the guideline development methods 5 5 6 6 6 7 5 5

2. Rate the overall quality of the guideline presentation. 5 5 5 6 7 6 5 4

3. Rate the completeness of reporting. 4 2 6 6 6 6 4 5

4. Rate the overall quality of the guideline recommendations 3 3 6 5 6 6 5 4

5. Rate the overall quality of this guideline 4 3 5 5 6 6 5 5

6. I would recommend this guideline for use in practice 3 3 6 5 6 7 4 4

7. I would make use of a guideline of this quality in my professional decisions. 3 3 6 6 6 7 4 4

Total 27 24 40 39 43 45 32 31

% 55 % 49% 82 % 80 % 88 % 92 % 65 % 63 %

27

Tableau C3 – Résumé de l’évaluation AACODS pour les énoncés de position retenus

Domaines Questions

AACE/ACE 2017

(Fonseca)

AAD 2013

ACR 2018

AGES 2017

(Baumgärtel)

BC Cancer 2019

(Nakashima)

BIRD 2018

(Franchimont)

CAG-CCC (2020)

(Moayyedi)

Diabetes Canada

2019

EBE 2017

(Roediger)

ECCO 2017

(Danese)

Évaluateurs : 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2

Compétence

Associé à une organisation réputée?

S S S S S S O O S S S S S S S S S S S S

Compétences professionnelles ou une expérience considérable


Ayant produit ou publié d’autres travaux dans le domaine?


Étant un expert reconnu, nommé dans d’autres sources?


Étant cité par d’autres? S S S S S S O O S S S S S S S S S S S S

Étant étudiant à un cycle supérieur, sous la supervision d’ « experts »?

S S S S S S N N S S S S S S S S S S S S

L’organisation est-elle réputée? N O N O O O S S N N O O N O O O N N O O

L’organisation est-elle une autorité dans le domaine?

O O O O O O S S O O O O O O O O O O O O

Présente-t-il une liste de références détaillée, bibliographie?

O O N N N O O O O O O O O O O O O O O O

Exactitude

L’objectif ou le résumé du document est-il clairement énoncé?

O N O O O O O O O O O O O O O O O O O O

Répond-il à l’objectif, le résumé correspond-il au contenu?

O S O O O O O O O N O O O O O O O O O O

La méthodologie est-elle précisée?

N N N N N N N N ? N N N O O O N O O ? O

La méthodologie est-elle respectée?

S S S S S S S S ? S S S O O ? S ? O ? O

Revue par les pairs? O O ? ? ? N O O ? N O ? O O ? N O O N ?

Édité par une autorité réputée? O O ? ? O N O O O N O O ? O O N O O O O

Soutenu par des références documentées et fiables?

O O N N O O O O O O O O O O O O O O O O

Représentatif des travaux dans le domaine?

O O O O O O O O O O O O O O O O O O O O

Si ce n’est pas le cas, le document constitue-t-il une contrepartie valide?

S S S S S S S S S S S S S S S S S S S S

Collectes de données explicites et répondent aux besoins?

O N ? ? O O O N ? O O O O O O O O O O O

Document est de source secondaire, se reporter à l’original.


28

Domaines Questions

AACE/ACE 2017

(Fonseca)

AAD 2013

ACR 2018

AGES 2017

(Baumgärtel)

BC Cancer 2019

(Nakashima)

BIRD 2018

(Franchimont)

CAG-CCC (2020)

(Moayyedi)

Diabetes Canada

2019

EBE 2017

(Roediger)

ECCO 2017

(Danese)

Évaluateurs : 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2

L’interprétation ou l’analyse est-elle exacte et objective?


Étendue Les limites sont-elles clairement énoncées?

N N N N N N N N ? N O N N N O N O O O N

Objectivité

La perspective de l’auteur est-elle claire?

? O O O O O N O O O O O O O O O ? O O N

La présentation du travail semble-t-elle équilibrée?

O O O O O O ? O O O O O O O O O O O O O

Date

Le document indique-t-il précisément une date relativement à son contenu?

O O O ? N N O O O O O O O O O O O O O O

Si le document n’est pas daté mais que sa date peut être vérifiée avec précision, existe-il une raison valide qui justifie l’absence de date?

S S S O S S S S S S S S S S S S S S S S

Des références contemporaines clés ont-elles été incluses?

O O N N O O O O O O O O O O O O O O O O

Portée

Le document est-il significatif (faisabilité, utilité, pertinence)?


Met-il la recherche en contexte? O O O N O N O N O O O O O O O O O O O O

Enrichit-il la recherche ou y ajoute-t-il quelque chose d’unique?


Renforce-t-il ou réfute-t-il une position actuelle?


Le domaine de recherche serait-il moins riche sans ce document?


Est-il intégral, représentatif, caractéristique?

O O N O O O O N O O O O O O O O O O O O

A-t-il une incidence? O O O O O O O O O O O O O O O O O O O O

Score

Nombre de réponses positives/total de question sans les réponses sans objet (S)

20/25 19/25 14/25 15/25 19/25 18/25 23/29 22/29 19/26 18/26 23/25 21/25 22/25 24/25 23/25 20/25 22/25 24/25 22/25 22/25

Résultat (%) 80 % 76 % 56 % 60 % 76 % 72 % 82 % 76 % 73 % 69 % 92 % 84 % 88 % 96 % 92 % 80 % 88 % 96 % 88 % 88 %

O : Oui; N : Non : S : Sans objet; ? : Inconnu

29

Tableau C3 – Résumé de l’évaluation AACODS pour les énoncés de position retenus (suite 1)

Domaines Questions

EMA 2019

ESMO 2016

(Tabernero)

EULAR 2018

(Wiek)

FDA 2017

HAS 2017

HKSR 2019 (Ho)

IBD/ESPGHAN 2019

(De Ridder)

IG-IBD 2019

(Fiorino)

ISOPP 2019

Biosimilar Medicines

2019

Évaluateurs : 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2

Compétence









Étant cité par d’autres? S S S S S S S S S S S S S S S S S S S S



L’organisation est-elle réputée? O O O O O O O O O O O O O O O O N N ? O


O O O O O O O O O O O O O O O O O O ? O


O O O O N N N N O O O O O O O O O O O O

Exactitude


O O O O O O ? N O O O O O O O O O O N N


O O O O O O ? S O O O O O O O O O O S S


N N N N N N ? N N N O O N N N N O N ? N


S S S S S S S S S S ? O S S S S O S S S

Revue par les pairs? ? N O O ? N ? ? N N O O N O O O ? ? ? ?

Édité par une autorité réputée? O O ? O O N ? O O O O O O O O O ? ? ? N


O O O O N N N O ? N O O O O O O O O O O






? O O O N O O N ? N O O O ? O O O O O O


S S S S S S S S S S S S S S S S S S O S

30

Domaines Questions

EMA 2019

ESMO 2016

(Tabernero)

EULAR 2018

(Wiek)

FDA 2017

HAS 2017

HKSR 2019 (Ho)

IBD/ESPGHAN 2019

(De Ridder)

IG-IBD 2019

(Fiorino)

ISOPP 2019

Biosimilar Medicines

2019

Évaluateurs : 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2


? O O O ? O O O ? O O O O O O O O O O O


? N O N N N ? N ? N O O O N O N N N O N

Objectivité


O O O O ? O ? O O O O O O O O O O O ? O


O O O O O O O O ? O O O O O O O O O O O

Date


O O O O O O O N O O O O O O O O O O O O


S S S S S S S N S S S S S S S S S S S S


O O O O ? N O N ? N O O O O O O O O O O

Portée



Met-il la recherche en contexte? O N O O O N O N O N O O O O O O O O O O


O O O O O O O O O O O O O O O O O O ? ?


O O O O O O O O O O O O O O O O O O ? N


O O O O O O O N O O O O O N O O O O ? N



A-t-il une incidence? O O O O O O O O O O O O O O O O O O ? ?

Score


19/25 20/25 22/25 22/25 15/25 16/25 15/25 13/25 16/25 17/25 24/25 25/25 22/25 20/25 23/25 22/25 21/25 19/25 13/25 14/25

Résultat (%) 76 % 80 % 88 % 88 % 60 % 64 % 60 % 52 % 64 % 68 % 96 % 100% 88 % 80 % 92 % 88 % 84 % 76 % 52 % 56 %

31


Domaines Questions

HIS 2018

NICE 2016

NRAS 2019

PNCG 2014

(Mularczyk)

Polish Expert Group, 2019

(Jahnz-Rozyk)

SAMAC 2017

SBOC 2018

(Fernandes)

SBR 2015

(Azevedo)

SCR 2019

SEFH 2018

(Martinez)

Évaluateurs : 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2

Compétence


S S S S O O S S S S S S S S S S S S S S







Étant cité par d’autres? S S S S O O S S S S S S S S S S S S S S



L’organisation est-elle réputée? O O O O S S N N N N O N O O O O O O N N


O O O O S S O O O O O O O O O O O O O ?


O O O N S N O O O O N O O O O O N N O O

Exactitude






N N O O N N N N O O N N N N N N N N N N


S S ? O S S S S O O S S S S S S S S S S

Revue par les pairs? N O ? ? N N O ? O O ? ? N O ? N O N O ?

Édité par une autorité réputée? O O O O O N ? ? O O O O O O O O O N ? ?


O O N ? O N O O O O O O O N O O N N O O


O O O O O O O O O O O O O O O O N N O O


S S S S S S S S S S S S S S S S S N S S


O O ? O ? O O N O O ? O O N O O ? O ? O



32

Domaines Questions

HIS 2018

NICE 2016

NRAS 2019

PNCG 2014

(Mularczyk)

Polish Expert Group, 2019

(Jahnz-Rozyk)

SAMAC 2017

SBOC 2018

(Fernandes)

SBR 2015

(Azevedo)

SCR 2019

SEFH 2018

(Martinez)

Évaluateurs : 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2


? O ? O ? O O O O O O O O O O O O O ? O


? N O N ? N N N N N ? N O N O N N N N N

Objectivité




O O O O O O O O O O O O O O O O ? O N O

Date


O O O O O O O O O O N O O O O O N N O O


S S S S S S S S S S S S S S S S S N S S


O ? O O O O O O O O ? O O N O O ? N O O

Portée


O O O O O O N N O O O O O O O O O O N N

Met-il la recherche en contexte? O O O O O O O O O O O O O N O O O O O N


O O O O O O N N O O O O O O O O O N N N


O O O O O O N O O O O O O O O O O O O O


O O O O O O N N O O O ? O O O N O N N N



A-t-il une incidence? O O O O O O N O O O O O O O O O O O N N

Score


20/25 21/25 20/25 21/25 21/27 21/27 15/25 15/25 23/25 23/25 17/25 19/25 22/25 19/25 22/25 20/25 15/25 13/25 13/25 13/25

Résultat (%) 80 % 84 % 80 % 84 % 78 % 78 % 60 % 60 % 92 % 92 % 68 % 76 % 88 % 76 % 88 % 80 % 60 % 52 % 52 % 52 %

33


Domaines Questions

SFDA 2018

(Halabi)

ACD 2013

ASCO 2018

(Lyman)

Évaluateurs : 1 2 1 2 1 2

Compétence


S S S S S S


S S S S S S


S S S S S S


S S S S S S

Étant cité par d’autres? S S S S S S


S S S S S S

L’organisation est-elle réputée? N N N N N N


? N O O O O


O O O N O O

Exactitude


O O O O O O


O O O O O O


N O N N N N


S O S S S S

Revue par les pairs? O O N N N O

Édité par une autorité réputée? O O ? N O O


O O ? O O O


O O O O O O


S S S S S S


O O ? N O O


S S S S S S

34

Domaines Questions

SFDA 2018

(Halabi)

ACD 2013

ASCO 2018

(Lyman)

Évaluateurs : 1 2 1 2 1 2


O O ? O O O


O N O N ? N

Objectivité


O O O O O O


O O O O O O

Date


O O O O O O


S S S S S S


O O ? N O O

Portée


O O O O O N

Met-il la recherche en contexte? O O O O O N


O O N N ? O


O O O N O O


O O O O O N


O O O O O O

A-t-il une incidence? O O O O O O

Score


21/25 22/25 15/25 14/25 19/25 18/25

Résultat (%) 84 % 88 % 60 % 56 % 76 % 72 %

35

ANNEXE D

Caractéristiques des études primaires retenues

Tableau D1 – Caractéristiques de Abdalla 2017

Auteur, année Abdalla et ses collaborateurs, 2017

Essai clinique

Nom (no) N.D.

Phase N.D.

Amendements au protocole

N.D.

Titre Long-term safety and efficacy of biosimilar infliximab among patients with inflammatory arthritis switched from reference product

Objectif To evaluate the efficacy and safety of the biosimilar infliximab in adult patients with inflammatory arthritis switched from reference product in our center.

Devis et méthode ENCAA

Population Nombre sujets inclus

N= 34 BR/BS n= 34

Critères inclusion

patients were enrolled without prespecified criteria. Any patient receiving the reference infliximab (Remicade™) was considered eligible for switching to the biosimilar infliximab. All patients were in remission at the time of switching.

Critères exclusion

Patients who are otherwise in remission continued to receive their biosimilar infliximab (Inflectra™) unless it was recommended to hold or discontinue therapy.

Caractéristiques sujets inclus

Intervention switched from the reference infliximab (Remicade®) to the biosimilar infliximab (CT-P13) in a real-life clinical setting. Doses were prescribed as per manufacturer according to the indication: rheumatoid arthritis the loading dose = 3 mg/kg at 0, 2, and 6 weeks, then every 8 weeks for maintenance, psoriatic arthritis the loading dose = 5 mg/kg at 0, 2, and 6 weeks then every 8 weeks for maintenance, ankylosing spondylitis the loading dose = 5 mg/kg at 0, 2, and 6 weeks then every 6 weeks for maintenance

Comparateur N.D.

Paramètres évalués (outcomes)

Principal Safety and efficacy

Secondaires N.D.

Milieu de dispensation des soins The rheumatology department at Unit 1, Merlin Park University Hospital, Galway

Durée du suivi 6 months before the switch (retrospective) up to mean (SD) = 15.8 (6.3) months.

Puissance N.D.

36

Auteur, année Abdalla et ses collaborateurs, 2017

Analyses statistiques

Type N.D.

Test All variables of interest were numerical in nature. SPSS version 22 (StataCorp LP, College Station, TX, USA) was adopted for data analysis. Descriptive statistics were used to report the differences in the outcome variables before and after use of the biosimilar infliximab (Inflectra™). The central tendency for the normally distributed data was expressed in mean (standard deviation), while nonnormally distributed continuous data was expressed in median (range). χ2 test was used to compare categorical variables. As all the data was collected before and after switching for the same patients, all tests were assumed to be paired (related). Continuous variables that are normally distributed were reported using parametric statistics (paired Student’s t-test) while nonparametric alternative (Wilcoxon signed-rank test) was used for nonnormally distributed data. Approximately 95% confidence intervals were reported for the mean differences before and after switching. p values below 0.05 were considered significant.

Conclusion générale des auteurs

Our patients who were switched from the reference to the biosimilar infliximab experienced comparable efficacy and safety profile over the follow-up period (15.8 months) without major safety issues in keeping with the other previous reports.10–12 Larger switching studies with longer follow-up duration are ongoing, and needed, to support these findings. Major cost savings are anticipated (30%–50%) with switching to biosimilar infliximab.

Financement de l’étude N.D.

Déclaration des conflits d’intérêts

Prof. John J Carey has received speaker fees from Hospira UK, Hospira Canada, Pfizer Canada, Pfizer Brazil. He has received education and research grants from Centocor, USA, MSD. Ireland and travel support from MSD Ireland. This work was presented as a poster abstract at the EULAR 2016 (European League Against Rheumatism) meeting in London, UK (DOI: 10.1136/annrheumdis- 2016-eular.2924). The authors report no other conflicts of interest in this work.

Approbation éthique N.D.

Qualité méthodologique ASPC : Faible

Tableau D2 – Caractéristiques de Alten 2019

Auteur, année Alten et ses collaborateurs, 2019

Essai clinique

Nom (no) NCT02222493

Phase 3


Patients enrolled under the original protocol could receive concomitant sulfasalazine and/or antimalarial drugs at a stable dose. A protocol amendment later removed these allowable background therapies and required a 4-week washout period prior to the first dose of study drug. Use of other DMARDs also required a washout period prior to the first dose of study drug.

Titre Randomised, double-blind, phase III study comparing the infliximab biosimilar, PF-06438179/GP1111, with reference infliximab: Efficacy, safety and immunogenicity from week 30 to week 54

Objectif to investigate the efficacy, safety and immunogenicity of PF-06438179/GP1111 (PF-SZ-IFX) compared with European reference infliximab (Remicade®; ref-IFX) in patients with moderate-to-severe, active rheumatoid arthritis after continued long-term use of PFSZ- IFX, and in patients who were switched from ref-IFX to PF-SZ-IFX.

Devis et méthode ECRA open label 174 centers in 28 countries


N= 650 BS n= 324, BS/BS n= 280 BR n= 326, BR/BR n= 143, BR/BS n= 143

Critères inclusion

Eligible patients were adults (aged ≥18 years) who met the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for RA for ≥ 4 months and ACR classes I–III functional status, based on the 1991 revised criteria [17, 18]. Patients had moderate to severe active RA, with at least six swollen and at least six tender joints at both screening and baseline, and high-sensitivity C-reactive protein (hs-CRP) ≥ 10 mg/L at screening. Patients must have received oral or parenteral MTX (10–25 mg/wk) for ≥ 12 weeks (at stable dose for ≥ 4 weeks) and oral folic/folinic acid (≥ 5 mg/wk) for ≥ 21 days prior to the first dose of study drug. Patients intolerant to 10–25 mg/wk could enroll with an MTX dose as low as 7.5 mg/wk. A dose of

37


6.0 mg/wk was allowed in geographic regions where specified by local guidance or standard of care.

Critères exclusion

The main exclusion criteria were current infection or infection requiring hospitalization or parenteral antimicrobial therapy judged clinically significant by the investigator ≤ 6 months prior to the first dose of study drug; evidence or history of congestive heart failure, demyelinating disease, untreated or inadequately treated latent or active tuberculosis, or malignancy within the past 5 years; inadequate bone marrow, liver, renal, and immune system function at screening; and positivity for human immunodeficiency virus, hepatitis B virus, or hepatitis C virus. Patients were excluded if they had current or prior treatment with infliximab or lymphocyte-depleting therapies (e.g., rituximab, alemtuzumab); however, they were allowed up to two doses of one nondepleting, non infliximab biologic if discontinued ≥ 12 weeks or five half-lives (whichever was longer) prior to the first dose of study drug.


PF-06438179/GP1111 (n=324)

Infliximab-EU (n=326)

Sexe n (%)

Femmes 258 (79.4) 264 (81.0)

Hommes 66 (20.4) 62 (19.0)

Age, mean (SD), years 52.8 (13.3) 52.8 (12.9)

Weight, mean (SD), kg 73.3 (19.8) 74.2 (20.0)

Body mass index, mean (SD), kg/m2

27.2 (6.4) 27.7 (7.0)

Ethicité n (%)

Blanc 257 (79.3) 247 (75.8)

Noir 5 (1.5) 9 (2.8)

Asiatique 46 (14.2) 45 (13.8)

autre 15 (4.6) 25 (7.7)

Non spécifié 1 (0.3) 0

Région géographique n (%)

North American and Western Europe

50 (15.4) 51 (15.6)

Japan 24 (7.4)

23 (7.1)

South Korea 4 (1.2) 5 (1.5)

Latin America 22 (6.8)

22 (6.7)

Rest of the world 224 (69.1) 225 (69.0)

Intervention PF-SZ-IFX, Injections intraveineuses de 3 mg/kg à chaque 8 semaines Dose stable de méthotrexate (10–25 mg/sem) et acide folique /folinique pour la durée de l’étude

Comparateur Remicade®, Injections intraveineuses de 3 mg/kg à chaque 8 semaines Dose stable de méthotrexate (10–25 mg/sem) et acide folique /folinique pour la durée de l’étude


Principal Efficacité

Secondaires Effets indésirables, immunogénicité

Milieu de dispensation des soins 174 centers in 28 countries

Durée du suivi 24 semaines; Août 2014 à juin 2017


Puissance The study was powered (≥85%) to demonstrate equivalence using a prespecified symmetric margin of ±13.5% with a two-sided 95% CI when assuming ACR20 response rates of 57.5% at week 14 (TP1) in both arms.

Type En intention de traiter

Test The secondary efficacy endpoints were summarized using descriptive statistics, based on the intent-to-treat population, defined as all patients who were randomized to study treatment in TP2. Safety and immunogenicity endpoints were analysed descriptively for the safety population (all patients who received ≥1 dose of study drug in TP2). No formal

38


hypothesis testing was conducted for any secondary, safety or immunogenicity endpoints, or for any endpoints measured during TP2.


TP2 (weeks 30–54) of the REFLECTIONS B537-02 study demonstrated sustained treatment effect of PF-SZ-IFX comparable with that of ref-IFX, and continued to show the absence of clinically meaningful differences in efficacy, safety and immunogenicity between patients with moderate-to-severe, active RA remaining on PF-SZ-IFX or ref-IFX, or after a randomised, double-blind switch from ref-IFX to PF-SZ-IFX. These results add to the totality of evidence and further support the biosimilarity of PF-SZ-IFX compared with ref-IFX.

Financement de l’étude This study was sponsored by Sandoz and Pfizer.


RA has received honoraria and research grants from Bristol-Myers Squibb, Celltrion, Chugai Pharmaceutical, Eli Lilly, Janssen, Novartis, Roche and Pfizer. BB has received consulting fees, speaking fees and honoraria from Pfizer and Sandoz. TH has declared no conflicts of interest. HK has received consulting fees, speaking fees and/or honoraria from Asahi Kasei Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan KK, Janssen Pharmaceutical KK, Mitsubishi Tanabe Pharma, Novartis Pharma KK and Pfizer Japan, and research grants from AbbVie GK, Asahi Kasei Pharma, Astellas Pharma, Chugai Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, Novartis Pharma KK, Sanofi Pharma and UCB Japan. SCR has received research grants and consulting fees, speaking fees and/or honoraria from Pfizer. VT has no conflicts of interest. GB was an employee of Hexal (a Sandoz company) at the time of writing this manuscript. OvR is an employee of Hexal (a Sandoz company). CC, SH, MR and MZ are employees of Pfizer. SC has received consulting fees from Amgen, Boehringer- Ingelheim, Coherus, Merck, Pfizer and Sandoz and has received research grants from Amgen, Boehringer-Ingelheim, Coherus, Merck and Pfizer.

Approbation éthique The REFLECTIONS B537-02 study was conducted in accordance with the ethical principles of the Declaration of Helsinki and in compliance with all International Conference on Harmonisation Good Clinical Practice guidelines and was approved by the independent ethics committee or institutional review board of each study centre.

Qualité méthodologique ASPC: Moyenne

Tableau D3 – Caractéristiques de Argüelles-Arias 2017

Auteur, année Argüelles-Arias et ses collaborateurs, 2017

Essai clinique Nom (no) N.D.

Phase N.D.


N.D.

Titre Switching from reference infliximab to CT-P13 in patients with inflammatory bowel disease: 12 months results

Objectif Here, we assess the effectiveness and safety of switching to CT-P13 from infliximab reference product (RP) in patients with inflammatory bowel disease.

Devis et méthode ENCAA, prospective observational, 1 site, 1 country Spain


98

Critères inclusion

Patients with moderate to severe CD or UC who had previously been treated with and has responded to infliximab RP were included in the study

Critères exclusion

N.D.

39



Intervention All patients were switched to CTP13 (Remsima®; Celltrion, Incheon, South Korea) and treated according to the dosage and regime recommended by the Summary of Product Characteristics of Remsima® in Spain

Comparateur Infliximab RP (Remicade®; Janssen Biologics B.V., Leiden, The Netherlands)


Principal The efficacy endpoint was the change in clinical remission in patients switched from infliximab RP assessed at 12 months, according to the Harvey–Bradshaw (HB) score for patients with CD and the partial Mayo score for patients with UC.

Secondaires Adverse events (AE) were monitored from the first infusion of CT-P13 until the end of the study and were recorded according to the Office of Human Research Protection

Milieu de dispensation des soins Virgen Macarena Hospital (Seville, Spain)

Durée du suivi 0, 3, 6, 9 and 12 months


Puissance N.D.

Type Demographic and nominal results were reported in percentages and frequencies. Numerical results were reported as average and SD in cases of normal distribution and as median and interquartile range (IQR) in cases of skewed distribution.

Test The Cochrane’s Q test and the Friedman test were used to analyze the evolution of the clinical scores (HB score and partial Mayo score) and CRP values of patients. The 95% confidence intervals (95% CIs) were calculated and α was set at 0.05 for the determination of statistical significance.

Conclusion générale des auteurs In conclusion, this study provides valuable data on the long-term efficacy of CT-P13 maintenance treatment after switching from infliximab RP and demonstrates effectiveness and safety at 12 months.

Financement de l’étude Medical writing support was funded by Kern Pharma. Further editing support was provided by Alice Wareham PhD (Aspire Scientific Ltd, Bollington, UK) and funded by Celltrion Healthcare Co, Ltd.

Déclaration des conflits d’intérêts F Argüelles-Arias has participated in advisory boards and has received financial support to attend scientific meetings from Kern Pharma. M.F. Guerra Veloz, R. Perea Amarillo, L. Castro Laria, B. Maldonado Pérez, D. Chaaro Benallal, and A. Benítez Roldán have received financial support to attend scientific meetings from Kern Pharma. A. Vilches- Arenas, V. Merino, G. Ramírez, M.A. Calleja-Hernández, A. Caunedo Álvarez, and M. Romero Gómez have no conflicts of interest.

40


Approbation éthique The study was approved by the Research Ethics Committee of the Virgen Macarena Hospital.


Tableau D4 – Caractéristiques de Avouac 2018

Auteur, année Avouac et ses collaborateurs, 2018


Phase N.D.


N.D.

Titre Systematic switch from innovator infliximab to biosimilar infliximab in inflammatory chronic diseases in daily clinical practice: The experience of Cochin University Hospital, Paris, France

Objectif To investigate effectiveness of systematic switching treatment from innovator infliximab to biosimilar infliximab, and its associated factors.

Devis et méthode ENCAA - Prospective observational usual care study


260

Critères inclusion

Adults who agreed to switch to biosimilar infliximab, and who had received at least 3 infusions of innovator infliximab prior to the switch, were eligible for inclusion. All included patients agreed to participate in the study after informed consent, which was recorded in the medical source file.

Critères exclusion

N.D.


Global population,

N ¼ 260

RA, n ¼ 31

axSpA,

n ¼ 131

Other

rheumatic

diseases,

n ¼ 20

Crohn's

disease, n ¼ 41

Ulcerativ

e colitis,

n ¼ 23

Uveitis,

n ¼ 8

Other,

n ¼ 6 Age (y), mean

(SD) 47 (15) 61

(13)

49 (12)

55 (20) 38 (12)

38 (14) 34 (7)

35 (24) Gender (male),

n (%) 143 (55) 4

(13)

90 (69)

9 (45) 23 (56)

12 (52) 4 (50)

1 (17) BMI (kg/m2),

mean (SD) 26.2 (5.5)

27.9 (7.9)

26.1 (4.8)

26.3 (3.1) No data

No data 21.2 (2.6)

25.0 (8.6)

Disease duration (y), mean (SD)

15 (11) 20 (12)

16 (10)

15 (14) 11 (8)

10 (9) 6 (4)

17 (15) Charlson

Comorbidity score, mean (SD)

1.0 (1.1) 1.4 (0.7)

1.2 (1.9)

0.9 (0.8) 0.6 (1.2)

0.6 (0.8) 0.4 (0.7)

1.0 (1.5)

Corticosteroid treatment, n (%)

47 (18) 15 (48)

9 (7)

6 (30) 2 (5) 4 (14) 8 (100)

3 (50) Prednisone

equivalent dose (mg),

1.6 (5.9) 2.3 (2.5)

0.4 (1.5)

1.2 (2.3) 1.2 (6.4)

5.5 (15.2)

11.0 (11.9)

3.5 (4.0)

mean (SD) NSAID intake last 7 days, n (%)

38 (15) 4 (13)

28 (21)

5 (25) 0 (0) 0 (0) 0 (0)

1 (17) csDMARD, n

(%) 141 (54) 27

(87)

54 (41)

18 (90) 24 (59)

9 (38) 6 (75)

3 (50) Number of

biologics before Infliximab,

0.5 (1.0) 0.3 (0.8)

0.7 (1.0)

1.0 (1.9) 0.2 (0.5)

0.1 (0.2) 0.0 (0.0)

0.5 (1.2)

mean (SD) Etanercept, n 51 3 39 7 1 0 0 1 Adalimumab, n 63 0 44 5 8 5 0 1 Golimumab, n 6 0 5 1 0 0 0 0 Certolizumab, n 4 1 2 1 0 0 0 0 Abatacept, n 5 2 0 2 0 0 0 1 Tocilizumab, n 4 1 1 2 0 0 0 0 Anakinra, n 3 2 0 1 0 0 0 0 Rituximab, n 0 0 0 0 0 0 0 0 Usketinumab, n 1 0 0 1 0 0 0 0 Other, n 5 2 1 2 0 0 0 0

Intervention Infliximab biosimilar

Comparateur Infliximab innovator


Principal The primary outcome was the retention rate of biosimilar infliximab at the time of the third infusion, measured on the overall patient population.

Secondaires They included the retention rate of biosimilar infliximab at the last available visit (July 2016), measured in the overall population and in each department, changes in global activity score between baseline and the last visit (whole population), specific activity scores for each disease, infliximab trough levels, and occurrence of serious adverse events. Factors associated with biosimilar infliximab discontinuation at the last visit in July 2016 were explored.

41

Auteur, année Avouac et ses collaborateurs, 2018

Milieu de dispensation des soins Rheumatology, Gastroenterology, and Internal Medicine departments of Cochin Hospital

Durée du suivi Mean ± SD follow-up period was 33.9 ± 4.5 weeks


Puissance N.D.

Type All data are expressed as mean values ± standard deviation (SD) or number and percentage (%) for continuous and categorical variables, accordingly. Statistical analysis was performed using SAS.

Test Comparisons before-after switch were estimated by paired t-test or McNemar test for continuous and categorical variables, accordingly. Retention rate of biosimilar infliximab was estimated by Kaplan-Meier survival curves. Factors associated with discontinuation were estimated by Cox proportional hazards models.

Conclusion générale des auteurs In conclusion, our results confirm effectiveness of biosimilar infliximab with no major safety issues in a clinical practice setting. This work supports the adoption of switching from reference infliximab to biosimilar infliximab by scientific societies and Health providers in France.


Déclaration des conflits d’intérêts N.D.

Approbation éthique The protocol and the informed consent document have received Institutional Review Board/Inde- pendent Ethics Committee (IRB/IEC) approval before initiation of the study (“Comité de Protection des Personnes” Paris Ile de France I).


Tableau D5 – Caractéristiques de Belleudi 2019

Auteur, année Belleudi et ses collaborateurs, 2019

Essai clinique

Nom (no) N.D.

Phase N.D.


N.D.

Titre Effectiveness and safety of switching originator and biosimilar epoetins in patients with chronic kidney disease in a large-scale Italian cohort study

Objectif The objective of this study was to evaluate the effectiveness and safety of switching versus non-switching and of switching from originator/biosimilar epoetin alpha (ESA α) to any other epoetin in chronic kidney disease (CKD) patients.

Devis et méthode An observational, record-linkage, multi-database, retrospective cohort study 1 January 2009 and 31 December 2015


N= 14,400 BR n= 8843 BS n= 5557 BR/BS n=1559 BS/BR n=524

Critères inclusion

All subjects with at least one ESA α (originator) or biosimilar dispensing between 1 January 2009 and 31 December 2015 were considered. the study cohort was restricted to subjects without any ESA prescriptions in the 6 months before baseline (new users) and who were treated because they had a recorded diagnosis of CKD. Finally, patients who did not receive a second ESA dispensing within 120 days were discarded; this cut-off limit was chosen considering the mean duration of the therapy regimen recorded by the Therapeutic Plan Register.

Critères exclusion

N.D.

42



Intervention BR/BS switched from originator ESA α (originator; Eprex ®, Janssen-Cilag SpA, Milan, Italy) to biosimilar (Abseamed®, Medice Arzneimittel Pütter GmbH Co. KG, Iserlohn, Germany; Binocrit ®, Sandoz GmbH, Kundl, Austria; and Retacrit ®, Pfizer Europe MA EEIG, Bruxelles, Belgio) ou BS/BR Switch from biosimilar to originator

Comparateur BR/BR ou BS/BS Non-switchers


Principal Effectiveness and safety of ESAs

Secondaires N.D.

Milieu de dispensation des soins healthcare databases from four Italian areas, located in the central and southern part of the country, covering a total population of more than 12 million inhabitants.

Durée du suivi 1 January 2009 and 31 December 2015


Puissance N.D.

Type N.D.

Test The comparison of patients’ characteristics between switchers and non-switchers, before and after matching was performed within the two groups of ESA α users (i.e. originator or biosimilars). To assess the effectiveness and safety of switching, the adjusted hazard ratios (HRs) and related confidence intervals (CIs) were estimated by fitting Cox models within both ESA α originator and biosimilar initiators, using non-switchers as a reference group. Cox models were also fitted within by different switching subgroups and their matched non-switchers depending on the second ESA received within each initiator group: • from originator of ESA α to (1) biosimilars; (2) short acting patented epoetins; or (3) long-acting patented epoetins; and • from biosimilars of ESA α to (4) originator; (5) short acting patented epoetins; and (6) long-acting patented epoetins. In order to analyse the robustness of our results, the following sensitivity and subgroup analyses were carried out: • Analysis of the subgroup of subjects with a more conservative matching definition, i.e. reducing the duration of ESA α treatment from ± 30 days to ± 15 days, to increase the comparability between groups. • Restriction of the risk window for the switching occurrence, i.e. from 2 years to 180 days following the initiation of the first ESA α treatment. This would mitigate the time-dependent bias due to baseline adjustment. • Application of different definitions of follow-up, i.e. considering a fixed follow-up of 1 year and two different windows of follow-up (90 and 180 days). Finally, a comparison between the two switcher cohorts (i.e. switchers from originator to any other ESAs or from biosimilars to any other ESAs) was performed in terms of lack of effectiveness and safety. In this analysis, only switchers were selected and the cumulative probabilities of

43


observing an effectiveness or a safety event within each switching cohort for each category were estimated by Cox model, adjusting for baseline characteristics.


This large-scale observational study suggests that switching from ESA α to other ESAs in CKD patients is effective and safe when compared with non-switching, both within biosimilar and within originator initiators, and that switching from originator is effective and safe when compared with switching from a biosimilar in a real-world setting. These results may be very useful to support clinical decisions related to switching drug therapies and promote better health policies to improve the uptake of biosimilars in the population.

Financement de l’étude The study was conducted in the context of the “Assessment of Short- and Long-Term Risk–Benefit Profile of Biologics Through Healthcare Database Network in Italy” project coordinated by the University of Messina, funded by the Italian Ministry of Health. Only public researchers of the local and regional health authorities or academia were involved in the study.


Rosa Gini discloses a personal interest in sustainability of universal healthcare systems. Valeria Belleudi, Francesco Trotta, Antonio Addis, Ylenia Ingrasciotta, Valentina Ientile, Michele Tari, Maurizio Pastorello, Salvatore Scondotto, Pasquale Cananzi, Giuseppe Traversa, Marina Davoli and Gianluca Trifirò declare no conflict of interest.

Approbation éthique Compliance with Ethical Standards


Tableau D6 – Caractéristiques de Benucci 2017

Auteur, année Benucci et ses collaborateurs, 2017

Essai clinique

Nom (no) N.D.

Phase N.D.


N.D.

Titre Safety, efficacy and immunogenicity of switching from innovator to biosimilar infliximab in patients with spondyloarthritis: A 6-month real-life observational study

Objectif Switching from iINX to bINX offers cost savings but only limited evidence is available, and there are no guidelines. The aim of this study was to investigate the real-life efficacy, safety and immunogenicity of switching from innovator to biosimilar INX in patients with spondyloarthritis (SpA).

Devis et méthode ENCAA (Prospective observational study)


N= 41 BR/BS = 41 41 SpA patients (22 with AS, five with enteropathic arthritis, 10 with PsA and four with undifferentiated SpA)

Critères inclusion

Forty-one patients attending three Italian rheumatology centres with a previous diagnosis of SpA and clinically inactive or moderate disease activity (ASDAS-CRP\2.1; 22 with AS, five with enteropathic arthritis, 10 with PsA, and four with undifferentiated SpA), who had been treated for more than 6 months with innovator INX in accordance with the ASAS/EULAR guidelines, were switched to biosimilar INX for pharmaco-economic reasons (Tuscany Law No. 450 of 7 April 2015)

Critères exclusion

N.D.


Characteristics

Age, median (range), years 50,9 (23–80)

disease duration, median (range), months 124,5 (14–372)

duration of iINX treatment, median (range), months

73,7 (6–144)

Intervention who had been treated for more than 6 months with iINX and were switched to bINX for pharmaco-economic reasons

Comparateur S.O.

44

Auteur, année Benucci et ses collaborateurs, 2017




Milieu de dispensation des soins three Italian rheumatology centres

Durée du suivi 6 months (2015-2016)


Puissance N.D.

Type N.D.

Test Analysis of variance (ANOVA) was used in order to establish whether there were any significant differences between the mean values of all the considered variables at baseline and after 6 months of bINX treatment. ANOVA separates the variance of the data into between- and within group components, and F represents the ratio of the two estimates. If the F test p value is\0.05, there is a statistically significant difference between the mean values of all of the variables at a significance level of 5 %, and subsequent multiple range tests indicate which paired variables have significantly different mean values. The data were analysed using SAS statistical software, version 9.2. A p value of\0.05 was considered significant.


Our real-life experience shows that the switch from iINX to CT-P13 is feasible, safe and efficacious. It could also lead to savings useful for the sustainability of national healthcare systems, although a careful assessment of the adverse events and immunogenicity of the switch is still necessary.



N.D.

Approbation éthique The study was approved by the Ethics Committee of Ospedale San Giovanni di Dio (Florence, Italy), and all of the patients gave their informed consent.

Qualité méthodologique ASPC: Faible

Tableau D7 – Caractéristiques de Bergqvist 2018

Auteur, année Bergqvist et ses collaborateurs, 2018


Phase N.D.


N.D.

Titre Switching from originator infliximab to the biosimilar CT-P13 in 313 patients with inflammatory bowel disease

Objectif The aim of this study was to investigate the effectiveness and safety of switching IBD patients from treatment with Remicade® to CT-P13.

Devis et méthode This was a prospective observational open label multicentre cohort study of a structured nonmedical switch,


313

Critères inclusion

All adult patients with IBD on IFX therapy. All patients except one (99.7%) were on maintenance therapy.

Critères exclusion

N.D.

45



Intervention Biosimilar CT-P13 (Remsima®),

Comparateur O-IFX (Remicade®)


Principal The primary endpoint was change in disease activity at 2, 6, and 12 months after the switch, evaluated by the symptom-based scores Harvey–Bradshaw Index (HBI) for CD18 and the Simple Clinical Colitis Activity Index (SCCAI) for UC.

Secondaires Secondary endpoints were changes in disease activity in patients with and without concomitant immunomodulatory treatment; changes in quality-of-life parameters as measured by the Short Health Scale (SHS); changes in laboratory biomarkers including C-reactive protein (CRP), hemoglobin (Hb), albumin, and fecal (F) calprotectin; changes in pharmacokinetics and immunogenicity as measured by serum (S) IFX trough levels and presence of antidrug antibodies (ADAbs), respectively; the proportion of patients in clinical remission and in remission as defined by F-calprotectin, at time points 0, 2, 6, and 12 months; the proportion of patients in remission at baseline (time of switch; representing the status on O-IFX treatment) that had experienced loss of remission (LOR) at the given time points, defined by symptom-based scores and F-calprotectin levels; the proportion of patients with active disease at baseline that had gone into remission at the given time points; and the proportion of patients that experienced disease worsening (DW) at the given time points, irrespective of the patient’s level of disease activity at baseline.

Milieu de dispensation des soins four hospitals in the County of Skåne, Sweden

Durée du suivi 12 months

46



Puissance N.D.

Type Data are presented as mean (Mn) with standard deviation (SD) or as median (Md) with range or interquartile range (IQR).

Test For comparisons between baseline values and values at time points 2, 6, and 12 months, respectively, the paired samples Student’s t test was used for interval scale data or where the criteria for a parametric test were met. The Wilcoxon matched pairs signed rank test was used when data failed to meet the assumptions for a parametric test. The Chi-square test for trends was used to examine changes in frequency distribution of SHS sub-scores. In all analyses, p < 0.05 was considered statistically significant.

Conclusion générale des auteurs In conclusion, we have demonstrated that switching from Remicade® to CT-P13 may be done with preserved therapeutic effectiveness and safety in patients with IBD.

Financement de l’étude This work was supported by the Hedlund Foundation, the Julin Foundation, the Consul Thure Carlsson Foundation, the Bengt Ihre Stipend, the Swedish Society for Medical Research, the Royal Physiographic Society of Lund, Skåne University Hospital donations, the Swedish Society of Medicine, research support from the Healthcare Region of Southern Sweden, and grants to researchers in public health care from the Swedish Government (ALFSKANE-539811) to Jan Marsal.

Déclaration des conflits d’intérêts Leif Angelison has received lecturing fees from Takeda. Olof Grip has received consulting fees from Ferring, Janssen-Cilag, Takeda, and Viphor Pharma. Erik Hertervig has served as a speaker, a consultant, or an advisory board member for AbbVie, Merck, Sharp & Dohme (MSD), and Takeda. Stefan Nilson has served as a consultantfor Otsuka. Jan Marsal has served as a speaker, a consultant, or an advisory board member for AbbVie, Bristol-Myers Squibb, EuroDiagnostica, Ferring, Hospira, Janssen-Cilag, MSD, Otsuka, Pfizer, Sandoz, Takeda, Tillotts, and UCB Pharma. Jan Marsal has received investigator-initiated study funding from AbbVie, Ferring, and Pfizer. The other authors have no financial conflicts of interest.

Approbation éthique The study was performed in accordance with the Declaration of Helsinki and was approved by the regional ethics committee in Lund, Sweden (DNR2017/292).


Tableau D8 – Caractéristiques de Blackwell 2018

Auteur, année Blackwell et ses collaborateurs, 2018

Essai clinique

Nom (no) PIONEER (NCT01519700)

Phase 3


N.D.

Titre Safety and efficacy of alternating treatment with EP2006, a filgrastim biosimilar, and reference filgrastim: A phase III, randomised, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy

Objectif To further evaluate the data on switching of biosimilar filgrastim (ZarzioVR /ZarxioVR /EP2006) with reference filgrastim, here we present the results of an analysis of patients included in the study who received reference filgrastim, and a combined group of patients receiving switched treatment with either reference and then biosimilar, or biosimilar and then reference

Devis et méthode ECRA phase 3 double-blind, parallel group,


N= 214 BR n= 52 BS n=53 BR/BS/BR/BS ou BS/BR/BS/BR n=109

Critères inclusion

Women aged ≥18 years with histologically proven breast cancer eligible for treatment with docetaxel 75mg/m2, doxorubicin 50mg/m2 and cyclophosphamide 500mg/m2 [TAC regimen, risk of febrile neutropenia (FN): 22%–25%. Key inclusion criteria were Eastern Cooperative Oncology Group (ECOG) performance status_2 and adequate bone marrow function on day 1 of cycle 1 before chemotherapy.

Critères exclusion

Exclusion criteria included history of myelogenous leukemia, myelodysplastic syndrome or concomitant sickle cell disease, concurrent or prior radiotherapy within 4 weeks of

47


randomization, use of prophylactic antibiotics, prior chemotherapy or anticancer treatment of breast cancer or previous G-CSF therapy. (Reference 8)


Intervention BR/BS (filgrastim ZarzioVR /EP2006) Ou BS/BR Filgrastim (originator or biosimilar) was administered (5 ug/kg body weight/day, s.c.) from day 2 of each cycle until the absolute neutrophil count (ANC) recovered to 10x109/l after its nadir or for a maximum of 14 days. over six chemotherapy cycles

Comparateur BR/BR (filgrastim, Neupogen®, Amgen) Filgrastim (originator or biosimilar) was administered (5 ug/kg body weight/day, s.c.) from day 2 of each cycle until the absolute neutrophil count (ANC) recovered to 10x109/l after its nadir or for a maximum of 14 days over six chemotherapy cycles La branche BS/BS n’a pas été utilisée pour les analyses


Principal Effectiveness and safety

Secondaires Immunogenicity was also assessed.

Milieu de dispensation des soins 26 oncological centers in 6 countries

Durée du suivi December 2011 to June 2013


Puissance N.D.

Type N.D.

Test Evaluation of non-inferiority in overall FN rates between switching and non-switching groups was based on a non-inferiority margin of 15%, in line with FDA guidance [9]. The non-inferiority margin of 15% was selected based on the fact that filgrastim treatment was known to reduce the incidence of FN by approximately 30% as compared with no

48


granulocyte colony-stimulating factor (G-CSF) support. The non-inferiority margin of 15% was thus chosen to maintain>50% of the known effect size of filgrastim treatment. All statistical analyses were carried out using SAS (SAS Institute, Cary, NC).


In conclusion, this study showed that there are no clinically meaningful differences regarding efficacy, safety or immunogenicity when switching from reference to biosimilar filgrastim/ EP2006, or vice versa, and that switching can be carried out without cause for concern.

Financement de l’étude Sandoz GmbH, Austria (no grant numbers apply).


NH has provided advisory or consulting services to Amgen and Hexal AG. KB has provided advisory or consulting services to Sandoz GmbH, Kundl, Austria. AK and SG are employees of Hexal AG (a Sandoz company), Holzkirchen, Germany and YL is an employee of Sandoz, Inc., Princeton, NJ, USA. The remaining author has declared no conflicts of interest.

Approbation éthique The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Study protocols were reviewed by Independent Ethics Committees for each centre. All patients provided written informed consent.


Tableau D9 – Caractéristiques de Blauvelt 2018

Auteur, année Blauvelt et ses collaborateurs, 2018

Essai clinique


Phase 3


N.D.

Titre Phase III randomized study of the proposed adalimumab biosimilar GP2017 in psoriasis: Impact of multiple switches

Objectif To assess the impact of multiple switches between GP2017 and reference adalimumab (ref-ADMB) following the demonstration of equivalent efficacy and similar safety and immunogenicity, in adult patients with active, clinically stable, moderate-to-severe plaque psoriasis.

Devis et méthode ECRA phase III confirmatory study consisting, double blinded;


N= 465 TP1: BR n= 234; BS n= 231 TP2 + EP: BR/BR n= 127 BR/BS/BR/BS/BR n= 63 BS/BS n= 126 BS/BR/BS/BR/BS n= 63

Critères inclusion

≥ 18 years of age with active, clinically stable, moderate-to-severe chronic plaque psoriasis for ≥ 6 months, defined as PASI ≥ 12, Investigator’s Global Assessment (IGA) score ≥ 3 and ≥ 10% body surface area affected by plaque psoriasis. Other criteria included treatment with prior phototherapy or systemic psoriasis therapy, or suitability for such therapies.

Critères exclusion

Patients with other forms of psoriasis or drug induced psoriasis were not eligible.

49



Intervention BR/BS switched from Innovator adalimumab to Biosimilar GP2017

Comparateur BR/BR Innovator adalimumab


Principal Efficacity PASI 75 response at week 16

Secondaires Safety, immunogenicity

Milieu de dispensation des soins 73 study centres Bulgaria, France, Slovakia and the U.S.A.

Durée du suivi 51 weeks December 2013 and March 2015


Puissance The sample size was calculated based on PASI 75 response rates reported in prior clinical trials with ref-ADMB

Type Per protocol

Test For the primary objective, comparison of GP2017 and ref-ADMB, therapeutic equivalence was confirmed if the 95% confidence interval for the difference in PASI 75 response rates between treatments at week 16 was contained within a margin of 18%.

50


Assuming a dropout or major protocol deviation rate of 15%, and a 3% difference between treatments, a sample size of 448 patients (to maintain 380 evaluable patients) was required to provide a power of 90% to show equivalence between treatments. The study was powered for the primary and key secondary objectives (Appendix S1; see Supporting Information); all other results, including those associated with multiple switching, are descriptive in nature only. In line with guidance from the U.S. Food and Drug Administration (FDA), efficacy analyses were conducted using the per protocol analysis set. The per protocol set is considered conservative, as protocol violators who could bias study results towards equivalence are excluded.11 Supportive analyses were performed using the full analysis set. Safety data were analysed using the safety analysis set (Table S1; see Supporting Information).


The results support emerging data on switching, from clinical trials and registries in many indications.2,3,16,23–26 For example, in the recent NOR-SWITCH study, single switches from reference to biosimilar infliximab in patients with Crohn disease, ulcerative colitis, ankylosing spondylitis, rheumatoid arthritis, PsA and psoriasis were not inferior to continued treatment with the reference medicine, and safety and immunogenicity were similar between patients who switched or continued treatment

Financement de l’étude The study was funded by Hexal AG, a Sandoz company. The funder had a role in the study design, data collection, data analysis and manuscript preparation


A. Blauvelt has served as a scientific adviser and clinical study investigator for AbbVie, Allergan, Amgen, Boehringer Ingelheim, Celgene, Dermira Inc., Eli Lilly and Company, Janssen, Merck Sharp & Dohme, Novartis, Sandoz, UCB Pharma and Valeant; and as a paid speaker for Eli Lilly and Company and Janssen. J.P.L. has served as a clinical study investigator for Sandoz and has received a grant from University Hospital Nice. J.F.F. has served as a clinical study investigator for and has received research grants from Sandoz. J.M.W. served as a clinical study investigator for and has received research grants from Sandoz and has received research grants and honoraria from Novartis. D.G. has served as a clinical study investigator for Sandoz. E.S., J.J.L. and A. Balfour are employees of Hexal AG (a Novartis Division). C.L.L. has served as a consultant or advisory board member for AbbVie, Amgen, Boehringer Ingelheim, Dermira, Eli Lilly and Company, Janssen, LEO Pharma, Pfizer, Sandoz, VCB and Vitae; as an investigator for Actavis, AbbVie, Amgen, Boehringer Ingelheim, Celgene, Coherus, Cellceutix, Corrona, Dermira, Eli Lilly and Company, Galderma, Glenmark, Janssen, LEO Pharma, Merck, Novartis,

Approbation éthique conducted in accordance with the ethical principles of the Declaration of Helsinki and approved by the independent ethics committee or institutional review board for each study centre. An independent data monitoring committee was responsible for monitoring safety and study conduct. All patients provided written informed consent before entering the study.

Qualité méthodologique ASPC: Élevée

Tableau D10 – Caractéristiques de Blevins 2019

Auteur, année Blevins et ses collaborateurs, 2019

Essai clinique

Nom (no) INSTRIDE 3 study (NCT02666430)

Phase 3


N.D.

Titre Efficacy and safety of MYL-1501D versus insulin glargine in people with type 1 diabetes mellitus: Results of the INSTRIDE 3 phase 3 switch study

Objectif To assess the efficacy, insulin dose, safety and immunogenicity when people with type 1 diabetes mellitus switched between MYL-1501D and reference insulin glargine (Lantus®; Sanofi-Aventis US LLC, Bridgewater, New Jersey).

Devis et méthode ECRA phase 3 open-label, randomized, parallel-group,


N= 127 BR/BR n= 63 BR/BS multiple n= 64

Critères inclusion

Individuals with Type 1 Diabetes Mellitus, who successfully completed 52 weeks of reference insulin glargine treatment in the INSTRIDE 1 study (NCT02227862)13 and provided written informed consent were eligible.

51


Critères exclusion

Individuals were excluded if they had a history of clinically significant infections, had moderate insulin resistance (requiring basal plus prandial insulin of ≥1.5 U/kg/d), or planned to receive elective surgery requiring hospitalization or another investigational drug during the study period.


Intervention BR for 52 weeks (INSTRIDE 1 study, Lantus®) BR/BS (MYL-1501D Mylan's insulin glargine) 12 weeks, BR/BS/BR 12 weeks, BR/BS/BR/BS 12 weeks Both treatments were administered as subcutaneous injections via prefilled disposable pens, with initial study doses of MYL-1501D and reference insulin glargine administered at a dose adapted to the actual blood glucose levels of the participants. Participants also received disposable pens for subcutaneous injection of insulin lispro (Humalog®; Eli Lilly and Company, Indianapolis, Indiana) at mealtimes.

Comparateur BR for 52 weeks (INSTRIDE 1 study), insulin Lantus® BR/BR Insulin glargine for 36 weeks


Principal demonstrate equivalence between the two treatment sequences was change in HbA1c from baseline to week 36.

Secondaires Secondary endpoints included change from baseline in fasting plasma glucose (FPG), eight-point self-monitored blood glucose (SMBG) profile and insulin dose per unit body weight, and immunogenicity at week 36. AE were also assed.

Milieu de dispensation des soins 81 locations in 8 countries

Durée du suivi 40 weeks (December 2015 to March 2017)


Puissance N.D.

Type Modified intention-to-treat

Test The primary endpoint analysis was performed using the modified intention-to-treat population (mITT; all randomized participants who had at least one baseline and one post-baseline HbA1c value between weeks 24 and 36). Analysis of covariance was used to produce a 95% confidence interval (CI) for the difference between the two treatment sequence groups for the mean change from baseline in HbA1c. Equivalence of MYL-1501D to reference insulin glargine was established if the 95% CIs were within ±0.4% equivalence limits. Secondary endpoint analyses were performed using the intention-to-treat population, which included all randomized participants who had a baseline visit and at least one post-baseline visit. Treatment sequence group comparisons for secondary efficacy analysis were performed using a mixed-effects model approach. Safety analyses included participants who were randomized and took at least one dose of study drug. The hypoglycaemic event rate was analysed using a similar mixed effects model method

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for treatment comparisons. For categorical data, treatment comparisons were performed using Fisher's exact or the chi squared test.


In conclusion, the INSTRIDE 3 study met its primary endpoint by demonstrating that the change from baseline to week 36 in HbA1c in participants switching between MYL-1501D and reference insulin glargine was statistically equivalent to that observed in participants receiving reference insulin glargine over a 36-week period. Overall, both treatment sequences were well tolerated, with no meaningful differences in immunogenicity. Together, the results of this study show that switching patients between MYL-1501D and reference insulin glargine resulted in similar efficacy and safety.

Financement de l’étude Financial support for this study was provided by Mylan Inc, Canonsburg, Pennsylvania, and Biocon Ltd, Bangalore, India. Editorial assistance was provided under the direction of the authors by Elizabeth A. Harvie, PhD, ELS and Jennifer Rossi, MA, ELS, MedThink SciCom, with support from Mylan Inc.


T.C.B. has received clinical research support from AstraZeneca, Eli Lilly, Lexicon, Merck, Mylan, Novo Nordisk and Sanofi. A.B., Y.R., P.A., B.S. and R.M. are paid employees of Mylan Inc. and may hold stock or stock options in the company. S.A. is a paid employee of Biocon Research Ltd and may hold stock or stock options in the company.

Approbation éthique The study was conducted in accordance with the general principles set forth in the International Ethical Guidelines for Biomedical Research Involving Human Subjects, the International Council for Harmonization Guidelines for Good Clinical Practice, the Declaration of Helsinki, and with applicable local regulatory requirements and laws. The protocol was reviewed and approved by independent ethics committees/ institutional review boards in accordance with local legal regulations. All participants provided written informed consent before study enrolment.


Tableau D11 – Caractéristiques de Bonifati 2019

Auteur, année Bonifati et ses collaborateurs, 2019

Essai clinique

Nom (no) N.D.

Phase N.D.


N.D.

Titre Effectiveness of etanercept biosimilar SB4 in maintaining low disease activity in patients with psoriatic arthritis switched from etanercept originator: An open-label one-year study

Objectif Our primary objective was to verify the ability of SB4 to maintain low disease activity in patients switching from reference etanercept to SB4 after 1 year of treatment with this last drug.

Devis et méthode ENCAA (Prospective observational study)


N= 87 BR/BS = 87 PsA patients

Critères inclusion

Eighty-seven adult PsA patients with stable (see below) low disease activity at baseline was non-mandatory switched from reference etanercept to SB4 and prospectively followed for 1 year. All patients were receiving treatment for psoriasis at our outpatient clinic where medical staff is composed of three dermatologists (CB, CDF, and VL) and 1 rheumatologist (DG).

Critères exclusion

N.D.

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Intervention Switched from Etanecept to SB4 50mg once weekly No patient was taking methotrexate at the start of the study.

Comparateur S.O.


Principal proportion of subjects who were previously treated with reference etanercept and maintained a cDAPSA score ≤ 13 after 1 year from switching to SB4.

Secondaires proportion of patients who maintained a cDAPSA ≤13 after 6 months; proportion of patients still in therapy with SB4 after 6 months and 1 year, respectively; reasons for SB4 discontinuation; proportion of patients who maintained an MDA 5/7 score after 6 months and 1 year, respectively; individual clinical index variations during the study.

Milieu de dispensation des soins Outpatient clinic, Italy

Durée du suivi 12 months (2016-2017)


Puissance N.D.

Type N.D.

Test Statistical analyses were performed through the use of GraphPad Prism version 6.00 for Windows, GraphPad Software, La Jolla, CA, www.graphpad.com and Analyse-it for Microsoft Excel version 2. 30; Analyse-it Software, Ltd. http://analyse-it.com/; 2012. McNemar, Kruskal–Wallis, and Mann–Whitney tests were used for comparisons, as necessary. Categorical data are presented as absolute numbers and percentages and continuous ones as medians and interquartile ranges (IQR). p Values< .05 were considered statistically significant. Loss of either cDAPSA13 or MDA 5/7 was analyzed using a non-responder imputation (NRI) procedure which included all subjects who, for whatever reason, failed to maintain a state of low disease activity or dropped out of the study.


In conclusion, our real-life data support the validity of switching from reference etanercept to SB4 for most patients. Moreover, we cannot exclude that improving communication between physicians and patients could contribute toward minimizing

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possible ‘nocebo effects’ and toward promoting the introduction of biosimilars in clinical practice.



The authors report no conflict of interest.

Approbation éthique All subjects signed a written informed consent form before switching from reference etanercept to SB4.


Tableau D12 – Caractéristiques de Bronswijk 2020

Auteur, année Bronswijk et ses collaborateurs, 2020

Essai clinique Nom (no) S.O.

Phase S.O.


S.O.

Titre Evaluating efficacy, safety, and pharmacokinetics after switching from infliximab originator to biosimilar CT-P13: Experience from a large tertiary referral center

Objectif The aim of this study was to investigate the pharmacokinetics, efficacy, and safety of a mandatory switch from IFX originator to CT-P13 in patients with CD and UC in a real-life setting.



BR/BS n = 361

Critères inclusion

all IBD patients who were switched collectively from the infliximab originator to CT-P13 in March 2017 were included

Critères exclusion

Patients with an ileostomy or ileal pouch-anal anastomosis were excluded.


Intervention Switch from infliximab to CT-P13

Comparateur S.O.


Principal The primary endpoint was IFX discontinuation for any reason within 6 months after the index infusion (first IFX infusion after March 2017).

Secondaires Secondary endpoints included loss of clinical remission, need for treatment optimization, development of adverse events, development of new ADAs, and evolution of PRO2, CRP, and IFX TLs.

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Auteur, année Bronswijk et ses collaborateurs, 2020

Milieu de dispensation des soins 1 tertiary referral center, Belgium



Puissance N.D.

Type N.D.

Test The IBM SPSS Statistics 25.0 software package (Armonk, NY, USA) was used for statistical analyses. For discrete data, proportions and percentages were reported, whereas for continuous data, medians with interquartile ranges (IQRs) were presented. To compare the evolution of TLs, PRO2, and CRP between time points, paired analyses were performed by using the Wilcoxon signed-rank test. We used χ 2 for categorical data and Mann-Whitney U test for continuous data in our univariate analysis. Multivariate analysis was performed by binary logistic regression. A 2-tailed P value < 0.05 was regarded as statistically significant.

Conclusion générale des auteurs Switching from IFX originator to CT-P13 did not lead to an increased rate of treatment discontinuation, loss of clinical remission, adverse events, or ADAs. With the increasing data of observational studies and recently published systematic reviews, switching from IFX originator to biosimilar CT-P13 seems safe and efficacious.

Financement de l’étude Fund for Scientific Research Flanders (TBM-T003716N).

Déclaration des conflits d’intérêts SV, GVA, and MF are senior clinical investigators of the Research Foundation Flanders (FWO), Belgium. GVA received a research grant from Abbvie and Pfizer; consultancy fees from Abbvie and MSD, Ferring, Takeda, Janssen, Pfizer, and Genentech/Roche; and lecture fees from Abbvie, Janssen, MSD, Takeda, Ferring, Dr. Falk Pharma, and Pfizer. SV received financial research support from MSD, Abbvie, Takeda, Pfizer and J&J; lecture fees from Abbott, Abbvie, Merck Sharpe & Dohme, Ferring Pharmaceuticals, UCB Pharma, Takeda, Pfizer, Hospira, Mundipharma and J&J; and consultancy fees from Abbvie, Takeda, Pfizer, Ferring Pharmaceuticals, Shire Pharmaceuticals Group, Merck Sharpe & Dohme, J&J, Gilead, Galapagos, Prodigest, Genentech/roche, and AstraZeneca Pharmaceuticals. AG received lecture fees from MSD, Janssen, Pfizer, Takeda, Novartis, and Abbvie, fincancial research support from Pfizer and MSD, and license agreements with R-Biopharm, apDia and Merck. MF received financial support for research from Janssen Biologics, Pfizer and Takeda; lecture fees from Abbvie, Amgen, Biogen, Boehringer-Ingelheim, Chiesi, Falk, Ferring, Janssen, Lamepro, Mitsubishi Tanabe, MSD, Pfizer, Takeda, Tramedico, Tillotts, Zeria; and consultancy fees from Abbvie, Boehringer-Ingelheim, Celltrion, Ferring, Janssen, Lilly, Mitsubishi Tanabe, MSD, Pfizer, Takeda. All other authors declare no conflicts of interest.

Approbation éthique The study was approved by the Institutional Review Board of the University Hospitals Leuven (B322201213950/S53684), and informed consent was obtained from all participants.


Tableau D13 – Caractéristiques de Buer 2017

Auteur, année Buer et ses collaborateurs, 2017


Phase N.D.


N.D.

Titre Switching from Remicade® to Remsima® is well tolerated and feasible: A prospective, open-label study

Objectif In this study, we aimed to prospectively investigate the feasibility, safety and immunogenicity of switching from Remicade® to Remsima® in a real-life IBD population.

Devis et méthode This is a prospective, open-label study from a single centre in Norway. Additionally, a retrospective registration of data with a start time of 6 months before switching was performed in the same patients


143

Critères inclusion

All adult [≥18 years] IBD patients in the IBD unit at Oslo University Hospital who were treated with Remicade® were switched to the biosimilar, Remsima®,

Critères exclusion

N.D.

56

Auteur, année Buer et ses collaborateurs, 2017


Intervention Remsima® (CT-P13)

Comparateur Remicade®


Principal The primary endpoints were [i] the proportion of patients remaining on medication 6 months after switching and [ii] adverse events during the 6 months after switching

Secondaires The secondary endpoints included [i] the development of ADAs, and [ii] changes in disease activity [HGBI and PMS], CRP, Hgb, FC, IFX dose and interval, and p-IFX.

Milieu de dispensation des soins Oslo University Hospital

Durée du suivi 6 mois


Puissance N.D.

Type All continuous data are expressed as the median (range or interquartile range [IQR]) or mean (standard deviation [SD]) when appropriate. Categorical data are presented as counts and percentages.

Test For the continuous variables CRP, Hgb, FC, p-IFX and mg/kg/week, the change over time before and after switch was analysed using linear mixed models for repeated measures. Fixed effects of time were estimated, and diagnosis, gender and age were included in the analysis as possible confounders. As all measurements were made at equally distributed time points, a diagonal covariate matrix was used to estimate dependencies between measurements. All overall effects were analysed using the F-test. The results are presented as estimated marginal means with 95% confidence intervals [CI]. Values of p<0.05 were considered statistically significant.

Conclusion générale des auteurs In conclusion, we have demonstrated that switching from Remicade® to Remsima® in a real-life IBD population is feasible and well tolerated with few adverse events, including very limited ADA formation and loss of response.

Financement de l’étude The data were generated as part of the routine work at the Department of Gastroenterology, Oslo University Hospital, and no specific funding was received for the study.

Déclaration des conflits d’intérêts MLH has received unrestricted Research grants from Takeda, Ferring and Tilotts and she has received speaker honoraria from MSD, MEDA and AbbVie. BM has been a member of advisory boards for Orion Pharma and Hospira. All other authors have no conflicts of interests.

Approbation éthique The study was approved as a quality assurance study by the local data protection officer. Only data from standard clinical follow-up were included in the study database, and all patients signed informed consent regarding their willingness to include their data in the study database.


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Tableau D14 – Caractéristiques de Cohen 2020

Auteur, année Cohen et ses collaborateurs, 2020

Essai clinique Nom (no) NCT02222493

Phase Phase 3


S.O.

Titre Long-term efficacy, safety, and immunogenicity of the infliximab (IFX) biosimilar, PF-06438179/GP1111, in patients with rheumatoid arthritis after switching from reference IFX or continuing biosimilar therapy: Week 54-78 data from a randomized, double-blind, phase III trial

Objectif Our objective was to evaluate the long-term efficacy, safety, and immunogenicity of the infliximab biosimilar, PF-06438179/GP1111 (PF-SZ-IFX), in patients with rheumatoid arthritis (RA) who continued biosimilar treatment throughout 78 weeks or who switched from reference infliximab (Remicade®) sourced from the EU (IFX-EU) at week 30 or week 54 in the REFLECTIONS B537-02 study.

Devis et méthode ECRA, double-blind, randomized, active-control, Extension


BR/BS n = 126

Critères inclusion

Inclusion Criteria: Diagnosis of rheumatoid arthritis based on 2010 ACR/EULAR criteria for at least 4 months. At least 6 tender (of 68 assessed) and 6 swollen (of 66 assessed) joints at screening and baseline. HS-CRP equal or greater than 10 mg/L. Must have received methotrexate for at least 12 weeks and be on a stable dose for at least 4 weeks.

Critères exclusion

Exclusion Criteria: Evidence of untreated or inadequately treated latent or active TB. Evidence or history of moderate or severe heart failure (NYHA Class III/IV) Infection requiring hospitalization or parenteral antimicrobial therapy judged clinically significant by the investigator within 6 months prior to first dose of study drug.


Intervention Switch from Infliximab to BS PF-06438179/GP1111

Comparateur S.O.


Principal Number of Participants with an American College of Rheumatology 20% (ACR20) Response at Week 14: Period 1 [Time Frame: Week 14] ACR20 response: greater than or equal to (>=) 20 percent (%) improvement in tender joint count (TJC); > = 20% improvement in swollen joint count (SJC); and > = 20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity (PGA); physician global assessment of disease activity; self-assessed disability (health assessment questionnaire-disability index [HAQ-DI]); and C-Reactive Protein (CRP).

58


Secondaires Number of Participants with an American College of Rheumatology 20% (ACR20) Response at Week 2, 4, 6, 12, 22 and 30 (Pre-dose): Period 1 [Time Frame: Week 2, 4, 6, 12, 22 and 30 (pre-dose)] ACR20 response: > =20% improvement in tender joint count; > =20% improvement in swollen joint count; and > =20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; HAQ-DI and CRP. Number of Participants with an American College of Rheumatology 20% (ACR20) Response at Week 38, 46 and 54 (Pre-dose): Period 2 [Time Frame: Week 38, 46 and 54 (pre-dose)] ACR20 response: > =20% improvement in tender joint count; > =20% improvement in swollen joint count; and > =20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; HAQ-DI and CRP. Number of Participants with an American College of Rheumatology 20% (ACR20) Response at Week 62, 70 and 78: Period 3 [Time Frame: Week 62, 70 and 78] ACR20 response: > =20% improvement in tender joint count; > =20% improvement in swollen joint count; and > =20% improvement in at least 3 of 5 remaining ACR core measures: participant assessment of pain; participant global assessment of disease activity; physician global assessment of disease activity; HAQ-DI and CRP. And 36 others.

Milieu de dispensation des soins 184 study centers located in the USA, Canada, Europe, Australia, South America, Korea

Durée du suivi 78-week August 2014 to June 2017


Puissance N.D.

Type N.D.

Test Treatment efficacy in TP3 was analyzed in the intent-to-treat (ITT) population, which included all patients enrolled and treated with one or more doses of study drug in TP3. Efficacy data were summarized using descriptive statistics for the ITT population. Safety and immunogenicity data were summarized descriptively for the safety population, which comprised all randomized patients who received one or more doses of study drug in TP3. Analyses were based on observed data collected in TP3; no imputation was applied to missing data during TP3. Data were analyzed for all patients and were evaluated in three groups in TP3 corresponding to the treatment sequence in TP1/TP2/TP3: biosimilar group (PF-SZ-IFX/PF-SZ-IFX/ PF-SZ-IFX), week 30 switch group (IFX-EU/PF-SZ-IFX/ PF-SZ-IFX), and week 54 switch group (IFX-EU/IFX-EU/ PF-SZ-IFX) (Fig. 1). Summary statistics for serum trough concentrations of PF-SZ-IFX were calculated by setting concentration values below the lower limit of quantification (LLOQ) to 0 (LLOQ = 100 ng/mL).

Conclusion générale des auteurs Results from TP3 of the REFLECTIONS B537-02 study showed patients with moderate-to-severe active RA receiving PF-SZ-IFX experienced no clinically meaningful differences in efficacy, safety, or immunogenicity, regardless of whether they were maintained on PF-SZ-IFX throughout 78 weeks of treatment or following single treatment transitions from IFX-EU to PF-SZ-IFX at week 30 or at week 54. PF-SZ-IFX was well-tolerated for up to 78 weeks of treatment and displayed a safety profile consistent with that of infliximab. These findings provide long-term clinical data to complement the existing evidence of similarity between reference infliximab and PF-SZ-IFX, including structure, biological function, pharmacokinetics, and therapeutic equivalence, and add to the “totality of the evidence” supporting biosimilarity of PF-SZ-IFX to reference infliximab and its use in the other eligible indications for which reference infliximab is authorized.

Financement de l’étude This study was sponsored by Pfizer Inc. Open access publication of this article was funded by Pfizer Inc.

Déclaration des conflits d’intérêts SBC has received research grants and consulting fees or honorarium from AbbVie, Amgen, Pfizer, and Sandoz. RA has no conflicts of interest that are directly relevant to the content of this article. HK has received consulting fees, speaking fees, and/or honoraria from AbbVie GK, Asahi Kasei Pharma, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan KK, Janssen Pharmaceutical KK, Mitsubishi Tanabe Pharma, Novartis, and Pfizer Japan and has received research grants from AbbVie GK, Asahi Kasei Pharma, Astellas Pharma, Chugai Pharmaceutical, Eisai, Mitsubishi Tanabe Pharma, and Novartis. AJK has received consulting fees and/or speaking fees and/or fees for participation on advisory committees or review panels from Sanofi, Regeneron, SUN Pharma Advanced Research, AbbVie, Janssen, Pfizer, UCB, Genzyme, Boehringer-Ingelheim, Celgene, Horizon, Merck, Novartis, and Flexion and has stock holdings for Pfizer, Sanofi, Amgen, and Gilead. MT has received research grants,

59


speaking fees, and honoraria from Pfizer Philippines. SCR has received research grants from Pfizer. OvR is an employee of Hexal AG (a Sandoz company). CC, SH, MIR, and MZ are employees of, and hold stock or stock options from, Pfizer.

Approbation éthique Compliance with Ethical Standards. The study was conducted in accordance with the ethical principles of the Declaration of Helsinki and in compliance with International Conference on Harmonisation Good Clinical Practice guidelines. The independent ethics committee or institutional review board for each study center approved the study protocol; an independent data monitoring committee was responsible for monitoring safety and study conduct. Informed Consent All patients provided written informed consent before study entry. No additional informed consent was required because the three treatment periods were part of the same study.


Tableau D15 – Caractéristiques de Cohen 2018


Essai clinique

Nom (no) VOLTAIRE-RA, NCT02137226

Phase 3


Region was not included in the model due to sparse data in some regions. This was known shortly after final recruitment and included in a protocol amendment prior to database lock.

Titre Similar efficacy, safety and immunogenicity of adalimumab biosimilar BI 695501 and Humira reference product in patients with moderately to severely active rheumatoid arthritis: Results from the phase III randomised VOLTAIRE-RA equivalence study

Objectif To demonstrate clinical equivalence of adalimumab biosimilar candidate BI 695501 with Humira®.

Devis et méthode ECRA double blind, parallel arm


N = 645 BS n= 324, BS/BS n= 298 BR n= 321, BR/BR n= 148, BR/BS n=147

Critères inclusion

Adults (18–80 years) with moderately to severely active RA for ≥6 months, defined by ≥6 swollen joints (66 joint count) and ≥6 tender joints (68 joint count), at screening and baseline, and either ESR > 28 mm/hour or C reactive protein (CRP) > 1.0 mg/dL at screening, were enrolled. Patients must have received 15–25 mg/week MTX background treatment for ≥12 weeks prior to enrolment. MTX 10–14 mg/week was permitted for patients intolerant to higher doses. Patients could have been on oral corticosteroids ≤10 mg/day prednisolone or equivalent (stable for 4 weeks prior to day 1) and stable non-steroidal anti-inflammatory drugs for 2 weeks prior to day 1.

Critères exclusion

Exclusion criteria included previous RA treatment with adalimumab or > 1 other biologic, active infection, hypersensitivity reactions or AEs to agents similar to the study drugs or their excipients (full criteria available in online supplementary appendix B).

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Intervention Adalimumab BS, BI695501 n=147 semaines 24-48 Receive BI 695501 40 mg subcutaneously by prefilled syringe once every 2 weeks for 24 weeks

Comparateur Adalimumab BR, Humira® (n=321) semaines 1-24, n=148 semaines 24-48 Receive Humira® 40 mg subcutaneously by prefilled syringe once every 2 weeks for 48 weeks


Principal The primary objective of the study was to demonstrate equivalent clinical efficacy of BI 695501 and Humira®. Coprimary endpoints were the percentage of patients achieving the American College of Rheumatology 20% response criteria (ACR20) at week 12 (requested by FDA) and week 24 (requested by EMA).

61


Secondaires Prespecified secondary endpoints were change from baseline in Disease Activity Score in 28 joints (DAS28) using erythrocyte sedimentation rate (ESR) at weeks 12 and 24, and the percentage of patients with drug-related treatment-emergent adverse events (AEs). Further endpoints included ACR-based and DAS-based parameters at various time points, quality of life (36-Item Short- Form Health Survey (SF-36) V.2), AEs (including infections/ serious infections, hypersensitivity reactions, drug-induced liver injury, injection site reactions) and immunogenicity (antidrug antibodies (ADAs), neutralising antibodies (nAbs), drug levels). The secondary efficacy endpoint of change from baseline in DAS28-ESR was assessed via an analysis of covariance model, using multiple imputation method for missing data. ACR20 at week 48, ACR50 and ACR70 and further efficacy endpoints were computed using the same missing data methodology. Exploratory endpoints were analysed by descriptive statistical methods.

Milieu de dispensation des soins in 14 countries (115 sites)

Durée du suivi 48 semaines; January 2015 to March 2016


Puissance For this test to be performed with adequate power (86%–91%), a sample size of ~650 patients were needed (FAS). This sample size was based on an assumed treatment difference in ACR20 response rates of 0%, a standard proportion of 59% and an asymmetrical equivalence margin of (−12% to 15%) at week 12, with corresponding values of 0%, 63% (−15% to 15%) at week 24. The FAS contained all patients who received at least one dose of trial drug and who had all measures required for the efficacy endpoints (ACR20 at weeks 12 and 24) at baseline and at least once postbaseline.

Type The per-protocol analysis set (PPS) contained all patients in the FAS who did not experience any important protocol deviations relevant for efficacy (eg, severe deviation to the restricted disease-modifying anti-rheumatic drug (DMARD) therapy prior to primary endpoint assessment).

Test For determination of the primary endpoint, non-responder imputation was used for patients who discontinued prior to that time point. For patients who had not discontinued but had missing data, multiple imputation was used. At each time point (weeks 12 and 24), and on each of the complete data sets following the imputation, logistic regression was applied, including fixed, categorical effects of treatment and prior exposure to a biologic agent (yes/no), and continuous effects of baseline DAS28-ESR. The multiple risk differences and CIs on the individual complete data sets were calculated using the Reeve method,7 and combined using Rubin’s rules.8 Region was not included in the model due to sparse data in some regions. This was known shortly after final recruitment and included in a protocol amendment prior to database lock. The primary endpoint, analysed as described above and based on the full analysis set (FAS), was met if the upper and lower CIs of both coprimary endpoints were contained within the prespecified margins. Equivalence was achieved when the difference in ACR20 response rates (BI 695501 minus Humira®) was within −12% and 15% (90% CI; week 12 per FDA consultation) and within −15% and 15% (95% CI; week 24 per EMA consultation). An FDA-agreed asymmetrical margin at week 12 was defined, with a slightly higher upper bound of +15% to allow for variations in techniques and response rates used in the calculation of the margins. The safety analysis set (SAF) contained all patients who received at least one dose of trial drug. Descriptive safety data were coded according to MedDRA V.19.0. Data were analysed using SAS software Version 5.0.


VOLTAIRE-RA showed that BI 695501 and Humira® are highly similar in terms of efficacy, safety and immunogenicity. The switch from Humira® to BI 695501 had no impact on efficacy, safety and immunogenicity. These data, together with the analytical and the phase I data, suggest that BI 695501 and Humira® are biosimilar and thus therapeutically equivalent.

Financement de l’étude Boehringer Ingelheim provided the funding and was responsible for the conduct of this study.


SBC and ECL received funding from Boehringer Ingelheim, study sponsor, as principal investigators of this study. AA-R and PAK have no competing interests to declare. NP, IS and DA are (or were) employees of Boehringer Ingelheim, study sponsor.

Approbation éthique The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the institutional review boards of all participating centres. All patients provided written informed consent.


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Tableau D16 – Caractéristiques de Eberl 2017

Auteur, année Eberl et ses collaborateurs, 2017


Phase N.D.


N.D.

Titre Switching maintenance infliximab therapy to biosimilar infliximab in inflammatory bowel disease patients

Objectif The objective of this study was to evaluate changes in TLs, ADA formation and disease activity after switching from originator infliximab to biosimilar one.

Devis et méthode ENCAA, prospective


78 patients (38 CD, 37 UC and 3 IBD-unclassified [IBD-u])

Critères inclusion

All IBD patients receiving IFX maintenance therapy

Critères exclusion

N.D.


Intervention Biosimilar IFX (Remsima®, Celltrion Pharm, Inc., South Korea)

Comparateur IFX (Remicade®, Janssen Biotech, Inc., /Schering-Plough, EU)


Principal IFX TLs and ADAs were measured before the last originator IFX infusion (baseline) and before the third biosimilar IFX infusion (follow-up).

Secondaires Blood samples for measurements of haemoglobin, leukocytes, platelets and serum C-reactive protein (CRP) were also taken at these time points. Faecal calprotectin (FC), partial Mayo score (PMS) and Harvey–Bradshaw index (HBI) were used to assess clinical disease activity

Milieu de dispensation des soins Helsinki University Hospital

Durée du suivi After 3 biosimilar IFX infusion, Median IFX infusion interval was 8 weeks (range 4–10 weeks).


Puissance N.D.

Type Laboratory values are presented as median and interquartile range (IQR). Disease activity is presented as mean and standard deviation (SD).

Test Wilcoxon Signed-Rank test served as exploring changes between related variables. For further analysis of TLs, we used the nonparametric two one-sided tests of equivalence for paired samples. Equivalence was established if the 95% confidence interval (CI) of the median difference in the TLs before and after switching fell within the equivalence boundaries. The boundaries were set to ± the median absolute deviation about the median of the baseline IFX TL of all patients, indicating that the change of TL after switch for a patient tends to be smaller than the baseline TL difference between the patients.

Conclusion générale des auteurs To conclude, in this study, TLs before and after switch did not differ significantly in CD patients, but a statistically significant decrease in TLs in UC patients occurred. The clinical relevance of this decrease remains unclear as we could not observe any changes in clinical disease activity or faecal calprotectin. No safety concerns occurred during switching.


Déclaration des conflits d’intérêts There is no conflict of financial interests

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Auteur, année Eberl et ses collaborateurs, 2017

Approbation éthique The study was approved by the ethics committee of the Helsinki University Hospital (Dnro 32/13/03/01/2016) and research study permission was received from the Hospital District of Helsinki and Uusimaa (HUS-170-2016-2).


Tableau D17 – Caractéristiques de Emery 2017

Auteur, année Emery et ses collaborateurs, 2017

Essai clinique


Phase open-label extension period of the phase 3 study


S.O.

Titre Long-term efficacy and safety in patients with rheumatoid arthritis continuing on SB4 or switching from reference etanercept to SB4

Objectif We analysed data from the open-label extension period of the phase 3 study to evaluate the efficacy, safety and immunogenicity of continuing SB4 (SB4/SB4) versus switching from ETN to SB4 (ETN/SB4). Long-term safety and efficacy were assessed up to week 100.

Devis et méthode ENCAA (ECRA double blind open-label extension period)


N = 596 BS n= 299, BS/BS n= 126 BR n= 297, BR/BS n= 119

Critères inclusion

Patients aged 18–75 years who have been diagnosed with RA according to the revised 1987 American College of Rheumatology (ACR) criteria for ≥6 months and ≤15 years prior to screening were eligible for the study. Patients had to have active disease defined as ≥6 swollen and ≥6 tender joints and either erythrocyte sedimentation rate (ESR) ≥28 mm/h or serum C reactive protein (CRP) ≥1.0 mg/dL despite methotrexate (MTX) treatment for ≥6 months (stable dose of 10–25 mg/week for ≥4 weeks prior to screening). Non-steroidal anti-inflammatory drugs and oral glucocorticoids (equivalent to ≤10 mg prednisolone) were permitted if received at a stable dose for ≥4 weeks prior to randomisation.

Critères exclusion

Major exclusion criteria consisted of previous treatment with any biological agents, history of lymphoproliferative disease, congestive heart failure (New York Heart Association Class III/IV) or demyelinating disorders, diagnosis of active tuberculosis (TB) and pregnancy or breast feeding at screening.

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Intervention SB4 pendant

Comparateur aucun



Secondaires safety

Milieu de dispensation des soins 73 centres across 10 countries in Europe, Latin America and Asia for the ECRA, and Czech Republic and Poland for the extension

Durée du suivi 52 weeks; June 2013 to April 2014


Puissance Given a two-sided α level of 0.05 and 80% power, the two-sided 15% equivalence margin required 438 patients for the per-protocol set (PPS). Assuming 20% loss of patients from the PPS, the study required a minimum of 548 randomised patients.

Type S.O.(Per-protocol for ECRA)

Test All data were analysed descriptively. Efficacy and safety data were analysed in the extended population, which comprised all patients who provided informed consent for the open-label extension period and received ≥1 dose of study medication in the open-label extension period. Efficacy data obtained up to week 52 were analysed retrospectively in this population. No imputation was made for missing data. Analyses were performed using SAS software, V.9.2 or higher (SAS Institute, Cary, North Carolina, USA).


SB4 was well tolerated and effective over 2 years in patients with RA. Switching from ETN to SB4 was not associated with treatment-emergent issues such as loss of efficacy

65


or increases in TEAEs or immunogenicity. Post marketing surveillance and registry studies are ongoing to monitor the efficacy and safety of SB4 in various indications

Financement de l’étude This study was funded by Samsung Bioepis Co., Ltd.


All authors received funding for clinical research from Samsung Bioepis. PE received consulting fees; JV, AS, PL, WP, BS, JH, and ZM received research grants and SYC and JG are full-time employee of Samsung Bioepis. In addition, PE reports receiving grant/research support from AbbVie and Pfizer and consultancy fees from AbbVie, Bristol-Myers Squibb, Pfizer, UCB, Merck Sharp & Dohme, Roche, Novartis, Takeda and Lilly; JV served on speakers bureaus for UCB, Pfizer, AbbVie and Merck Sharp & Dohme; PL received grant/research support from Roche, Merck Sharp & Dohme, Janssen, Novo-Nordisk, UCB, Pfizer, Novartis, GlaxoSmithKline, Bristol-Myers Squibb, served as paid instructor for Novo-Nordisk and served on speakers bureaus for Merck Sharp & Dohme, UCB, Roche and Amgen.

Approbation éthique This study was conducted in accordance with the Declaration of Helsinki and International Council for Harmonisation Good Clinical practice guidelines. Protocols were reviewed and approved by the independent ethics committee or institutional review board for each study centre. All patients provided written informed consent.


Tableau D18 – Caractéristiques de Fabiani 2019

Auteur, année Fabiani et ses collaborateurs, 2019


Phase S.O.


S.O.

Titre The role of biosimilars in uveitis: Long-term real-world outcomes of the switch from original to biosimilar TNF-alpha inhibitors

Objectif The aim of the study was to identify any change in the control of ocular inflammatory manifestations in patients with non-infectious uveitis after the switch from an originator anti-TNF-a biologic agent to a corresponding biosimilar.



BR/BS n = 37

Critères inclusion

Patients suffering from non-infectious uveitis consecutively undergoing the switch from anti-TNF-a originator to biosimilar biologic agents were retrospectively enrolled;

Critères exclusion

N.D.


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Auteur, année Fabiani et ses collaborateurs, 2019

Intervention originator anti- TNF-a biological agents to biosimilars as follows : Imraldi® (n =20 patients, 33 eyes involved) Flixabi® (n = 10 patients, 16 eyes involved) Inflectra® (n = 5 patients, 9 eyes involved) Benepali® (n = 2 patients, 4 eyes involved).

Comparateur S.O.


Principal The endpoints of the study corresponded to the identification of any: i) statistically significant difference in the frequency of ocular flares during the follow-up after the switch compared to the preceding 12 months by standardizing the rate of uveitis relapses as number of flares/ 100 patients/12 months; ii) statistically significant changes in the best corrected visual acuity (BCVA) and systemic corticosteroid intake (mg/day of prednisone or equivalent) between the time of the switch and the last follow-up visit; iii) statistically significant changes in the mean central macular thickness (CMT) and in the frequency of eyes with uveitic macular edema (UME) or retinal vasculitis at the last assessment (3-, 6- and 12-month follow-up visits) compared with the time of the switch.

Secondaires S.O.

Milieu de dispensation des soins 1 center in Italy

Durée du suivi 3 months in 20 patients, 6 months in 6 patients, 12 months in 11 patients.


Puissance N.D.

Type N.D.

Test Descriptive statistics included sample size, percentages, means, and standard deviations. Normality distribution of quantitative data was assessed by using Shapiro-Wilk test followed by pair wise comparisons with unpaired two-tailed t test or Mann-Whitney two tailed U test, as appropriate. For categorical variables, comparisons were performed with Fisher exact test for 2 × 2 or 2 × 3 contingency tables. Two tailed p-values < 0.05 were considered statistically significant.

Conclusion générale des auteurs The switch to biosimilars represents a feasible treatment choice associated with the maintenance of clinical efficacy in patients with non-infectious uveitis previously treated with the corresponding originator anti-TNF-a biologic agents.


Déclaration des conflits d’intérêts The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Approbation éthique The study has been approved by the local Ethics Committee of Azienda Ospedaliera Universitaria Senese, Siena, Italy (Ref. N. 14951). The study protocol was conformed to the tenets of the Declaration of Helsinki; informed consent was obtained from all patients enrolled. The studies involving human participants were reviewed and approved by Azienda Ospedaliera Universitaria Senese. The patients/participants provided their written informed consent to participate in this study.


Tableau D19 – Caractéristiques de Felis-Giemza 2019

Auteur, année Felis-Giemza et ses collaborateurs, 2019


Phase S.O.


S.O.

Titre Observational study of inflammatory arthritis treatment by etanercept originator switched to an etanercept biosimilar

Objectif The aim of the study was to assess the safety and efficacy of switching an etanercept originator to an etanercept biosimilar in rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, and ankylosing spondylitis patients.



BR/BS n = 162 Naïve/BS n = 6

Critères inclusion

RA meeting European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) classification criteria [10], AS diagnosed according to modified

67

Auteur, année Felis-Giemza et ses collaborateurs, 2019

New York criteria with sacroiliitis in X-ray radiography [11], PsA meeting Classification for Psoriatic Arthritis (CASPAR) criteria [12] and high disease activity despite first-step treatment according to EULAR recommendations for RA [13], EULAR/ ASAS (Assessment of Spondyloarthritis International Society) for AS [14], and EULAR/ASAS/GRAPPA (Group for Research and Assessment of Psoriasis and Psoriatic Arthritis) for PsA [14–16]. In this study patients already treated with etanercept originator were eligible for enrolment as well as biologic-naïve patients.

Critères exclusion

N.D.


Intervention Switch from etanercept to SB4

Comparateur S.O.


Principal The main focus of this study were reasons for biosimilar treatment discontinuation: loss of efficacy (LoE) or adverse events (AEs). Loss of efficacy was defined as aggravation in disease activity level or constantly high disease activity level measured with DAS28 for RA, upswing or constant BASDAI score > 4 for AS, and lack of response according to PsARC for PsA [17–19]. Subjective loss of efficacy (sLoE) was defined as aggravation of disease activity perceptible only by the patient without objective measurements. An adverse event was defined as a new health disorder that occurred during biosimilar treatment, confirmed by physical examination or medical history.

Secondaires S.O.

Milieu de dispensation des soins 1 center in Poland

Durée du suivi 3-6 months; The study was conducted from November 2016 to May 2017


Puissance N.D.

Type N.D.

Test N.D.

Conclusion générale des auteurs In our study, the etanercept biosimilar (SB4) turned out to be effective and well-tolerated in most patients, although in some of them the switching was associated with AEs or LoE, which eventually resulted in treatment discontinuation. In most of these cases, switching back to the originator resulted in control of the disease and the same switching tolerance as before the therapy. There is still a need for further investigation of results of switching between bio-originators and biosimilars. Also, in the situation of increasing access to novel biosimilars, switching between them requires further clinical observation and research.


Déclaration des conflits d’intérêts The authors declare no conflict of interest.

Approbation éthique Because of the selection of the drug’s provider based on the result of public bidding, permission from the Ethics Committee was not required.


68

Tableau D20 – Caractéristiques de Fiorino 2018

Auteur, année Fiorino et ses collaborateurs, 2018


Phase N.D.


N.D.

Titre Full interchangeability in regard to immunogenicity between the infliximab reference biologic and biosimilars CT-P13 and SB2 in inflammatory bowel disease

Objectif We aimed to determine whether antibodies to infliximab (ATI) in inflammatory bowel disease (IBD) patients cross-react with RMC, CT-P13, and SB2.

Devis et méthode BIOSIM-01 is a retrospective cohort study conducted at a single referral IBD center in Italy


34 patients undergoing different IFX treatments (16 CD, 13 UC, and 5 unclassified colitis), and 28 IFX-naïve patients (12 CD, 13 UC, and 3 unclassified colitis) were enrolled

Critères inclusion

100 consecutive adult patients (age ≥ 18 years) with an established diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC) treated with IFX (5 mg/Kg at 0, 2, 6 weeks and then every 8 weeks thereafter) were included

Critères exclusion

N.D.


Intervention Cohorte 1 : CT-P13

Comparateur Cohorte 1 : Remicade®


Principal Trough ATI and IFX Measurements

Secondaires N.D.

Milieu de dispensation des soins IBD center in Italy (Humanitas Clinical and Research Institute, Rozzano, Milan, Italy)

Durée du suivi N.D.


Puissance N.D.

Type median

Test Correlation coefficients were determined by Spearman’s test. Positive (PPA) and negative (NPA) percent agreements between tests were determined. Group comparisons were evaluated using Mann-Whitney U Test.

Conclusion générale des auteurs This study demonstrates for the first-time identical reactivity of ATI with the reference RMC and the 2 approved biosimilar molecules in patients with IBD. In light of the results, we conclude that CT-P13 and SB2 biosimilars could be interchangeable and that switching between biosimilars and their reference product will not lead to differences in ATI production.

Financement de l’étude Biogen provided the SB2 drug for this study, reviewed the manuscript, and provided feedback to the authors. The authors had full editorial control of the publication. We thank David Arteta for support with statistical analysis

Déclaration des conflits d’intérêts Gionata Fiorino served as a consultant and Advisory Board Member for MSD, AbbVie, Takeda, Janssen, Mundipharma, Sandoz, Pfizer; Mariangela Allocca served as an Advisory Board Member for Mundipharma; Daniel Nagore, Lorena del Rio, Javier Pascual, and Antonio Martinez are full time employees of Progenika; Silvio Danese has served as a speaker, consultant, and advisory board member for Schering-Plough, Abbott Laboratories, Merck, UCB-pharma, Ferring, Cellerix, Millenium Takeda, Nycomed, Pharmacosmos, Actelion, Danone, Alpha Wasserman, Genentech, Grunenthal, Pfizer, Astra Zeneca, Novo Nordisk, Cosmo Pharmaceuticals, Vifor, and Johnson & Johnson; the other authors have no competing interests.

69

Auteur, année Fiorino et ses collaborateurs, 2018

Approbation éthique The protocol was submitted, reviewed, and approved by the Local Ethical Committee, Humanitas Clinical and Research Institute, Rozzano, Milan, Italy (BIOSIM-01). It was approved on June 06, 2016 with number 1616. All patients signed an informed consent form


Tableau D21 – Caractéristiques de Genovese 2019

Auteur, année Genovese et ses collaborateurs, 2019

Essai clinique Nom (no) Period I, NCT02260791; Period II, NCT02405780

Phase Phase 3


S.O.

Titre FKB327, an adalimumab biosimilar, versus the reference product: Results of a randomized, Phase III, double-blind study, and its open-label extension

Objectif To compare the efficacy, serum drug concentrations, immunogenicity, and safety of FKB327 with the adalimumab reference product (RP) in combination with methotrexate in patients with moderate-to-severe, active rheumatoid arthritis (RA).

Devis et méthode ECRA, Period I was a multicenter, randomized, double-blind, Phase III, parallel-arm, active-comparator trial to demonstrate comparable efficacy and safety of FKB327 to RP.


Period I: n = 730 BR n = 363 BS n = 367 Period II: n = 645 BR/BR n = 213 BR/BS n = 108 BS/BS n = 216 BS/BS n = 108

Critères inclusion

included patients aged ≥ 18 years with active RA diagnosed according to the revised American College of Rheumatology (ACR) criteria (2010 version) ≥ 3 months prior to screening. Active RA was confirmed by at least six out of 68 tender joints and at least six out of 66 swollen joints at screening and baseline, and a C-reactive protein (CRP) level ≥ 10 mg/L at screening. Inclusion criteria included taking MTX (oral or parenteral) for ≥ 3 months prior to screening at a stable dose of 10–25 mg/week for ≥ 8 weeks, with concomitant folic acid dose of ≥5mg/ week. Stable doses for ≥ 4 weeks were required if concomitant oral steroids (≤ 10 mg/day prednisone or equivalent) or non-steroidal anti-inflammatory drugs (NSAIDs) were taken. For inclusion in the extension study (Period II; NCT02405780), patients were required to have completed all 24 weeks of the double-blind study (Period I), with a minimum of nine doses of study drug received, and continued stable, concomitant MTX and folate treatment. Patients should have shown an adequate clinical response according to the investigator.

Critères exclusion

The main exclusion criteria included prior treatment with RP or any adalimumab-containing biosimilar and/ or more than one bDMARD or targeted synthetic DMARD (tsDMARD) for RA; prior treatment with a TNF inhibitor for RA with primary lack of efficacy as the reason for discontinuation; use of intra-articular or parenteral steroids or DMARDs other than MTX within 28 days or more of screening, depending on half-life; ACR functional Class IV; presence of chronic or acute infection at screening, including human immunodeficiency virus (HIV), hepatitis B, hepatitis C, and active or untreated latent tuberculosis (TB); or any active autoimmune disease or joint disease other than RA or malignancy in the 5 years prior to screening that had not been curatively treated (except for fully excised carcinoma in situ of the cervix or basal cell carcinoma).

70



Intervention Switch from adalimumab to FKB327

Comparateur Adalimumab


Principal The primary endpoint of Period I (double-blind study) was the American College of Rheumatology (ACR20) response rate at week 24. Two sets of equivalence margins and confidence intervals (CIs) for the difference in the ACR20 response rate were applied in order to meet different requirements from regulatory authorities. Criterion 1 was an equivalence margin of ± 13% using 95% CI, and Criterion 2 was an equivalence margin of − 12 to + 15% using 90% CI based on advice received from EU Committee for Medicinal Products for Human Use and the US Food and Drug Administration, respectively. The primary objective of Period II was to compare the long-term safety of FKB327 and RP, which was assessed as for Period I. An important secondary objective was to compare the effect of switching between treatments on efficacy, safety, and immunogenicity assessments.

Secondaires Secondary endpoints of Period I included DAS28-CRP at week 24 (key secondary endpoint) with an equivalence margin of ± 0.6, and ACR20, ACR50, and ACR70 response rates over time. Trough serum drug concentrations were collected at week 0 and prior to dosing at weeks 2, 4, 12, 20, and 24, then summarized by treatment group. Serum concentrations of adalimumab were determined using a validated immunoassay on an electrochemiluminescence (ECL) platform with a lower limit of detection of 100 ng mL− 1. ADA activity blood samples were collected at week 0 and prior to dosing at weeks 2, 4, 12, and 24. A highly sensitive ECL bridging format (Meso Scale Discovery) with acid dissociation to increase drug tolerance was used for immunogenicity assessments, which included the proportion of ADA-positive patients in each group, and ADA titer. ADA titer was defined as low (less than or equal to the lower quartile),

71


moderate (between the lower and upper quartile, both not included), or high (greater than or equal to the upper quartile). Subgroup analyses by ADA titer were conducted of ACR20 response rate, DAS28-CRP at weeks 24 and 54, and changes in DAS28-CRP from baseline. The effects of maximum ADA titer on serum drug concentrations in each treatment arm were analyzed over 54 weeks. The percentage of patients with neutralizing ADAs was assessed by sensitive competitive ligand binding. Since these were competitive ligand binding assays, they were able to detect new and additional ADAs throughout both study periods, even in patients with high titers.

Milieu de dispensation des soins Patients were recruited from 109 sites located in 12 countries (Bulgaria, Canada, Chile, Czech Republic, Germany, Peru, Poland, Romania, Russia, Spain, Ukraine, and the USA).

Durée du suivi 54 weeks


Puissance N.D.

Type N.D.

Test The full analysis set (FAS), used for efficacy analyses, was defined as patients who received at least one dose of treatment and who had at least one evaluable primary efficacy measurement. For the primary analysis, the 90% and 95% CIs for treatment difference in the ACR20 response rate at week 24 in Period I were calculated using a normal approximation method and missing values were imputed using root cause imputation and non-responder imputation. ACR20, ACR50, and ACR70 response rates were summarized using percentages and 95% CIs via the Clopper–Pearson method. DAS28-CRP was summarized using descriptive statistics. The 95% CI for treatment difference of DAS28-CRP at week 24 was calculated based on a mixed model for repeated measures with terms for stratification variables, site, visit, treatment, and treatment by visit interaction to demonstrate equivalence. For long-term efficacy evaluation in the extension study, descriptive statistics were calculated. Patients were included in the serum drug concentration analysis set if they had received at least one dose of study treatment and had at least one serum drug concentration result after treatment. Trough serum drug concentrations were summarized using descriptive statistics. The safety analysis set (SAS), defined as patients who received at least one dose of treatment, was used for safety and immunogenicity analyses. Datasets and outputs were produced using SAS® version 9.1 or higher.

Conclusion générale des auteurs In conclusion, the Phase III double-blind study met its primary and overall objectives by demonstrating comparability of FKB327 and RP in terms of efficacy, safety, and immunogenicity results. No effect of switching between FKB327 and RP treatments was observed in the extension study, and overall, these results support the proposal of FKB327 as a candidate biosimilar to RP in patients with active RA.

Financement de l’étude The study was funded by Fujifilm Kyowa Kirin Biologics Co., Ltd. (JAPAN).

Déclaration des conflits d’intérêts MCG has received grants from AbbVie, Amgen, and Pfizer. MCG has also received consulting fees from AbbVie, Amgen, Boehringer Ingelheim, Galapagos, FKB, Gilead, UCB, Merck, Samsung, Novartis, Regeneron, and Sanofi. JG has received personal fees from FKB. MG reports grants from Fujifilm, AbbVie, Amgen, Gilead, Lilly, Merck, and Pfizer during the conduct of the study, and other funds from Lilly, Pfizer, and Gilead outside of the study. JIV reports personal fees from Syneos Health Clinical Solutions during the conduct of the study. MS has received personal fees from AbbVie, Amgen, Boehringer Ingelheim, Fujifilm, Galapagos, Gilead, Merck, Lilly, Novartis, Pfizer, Regeneron, Samsung, and Sanofi during the conduct of the study. EB has received personal fees from Abbott, Bayer, Boehringer Ingelheim, Servier, and Berlin-Chemie Menarini. RA has received grants from Amgen and Pfizer. RA has also received consulting fees from AbbVie, Amgen, Boehringer Ingelheim, Galapagos, FKB, Gilead, Lilly, UCB, and Novartis. WP, ECEK, HK, MK, and ED declare that they have no competing interests.

Approbation éthique The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. The United States of America Quorum Review independent review board approved the study (approval number 29659). Approval was obtained for each of the study sites (109 in total), and all patients provided written informed consent.


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Tableau D22 – Caractéristiques de Gervais 2018

Auteur, année Gervais et ses collaborateurs, 2018


Phase N.D.


N.D.

Titre Switching from originator to biosimilar infliximab in paediatric inflammatory bowel disease is feasible and uneventful

Objectif The safety, clinical efficacy, and cost-effectiveness of biosimilar infliximab in adult inflammatory bowel disease (IBD) have now been extensively shown. Limited data have been collected in the paediatric setting.

Devis et méthode Prospective clinical data were collected on patients from all 3 Scottish regional services


39

Critères inclusion Patients who were receiving originator infliximab in 2016 or 2017 were identified and each case discussed within the wider multidisciplinary team. All patients were then provided with an ‘‘opt out’’ letter and an information sheet on biosimilar infliximab.

Critères exclusion N.D.


Of the 33 patients included, 16 (48%) were girls, 26 with CD, 4 with ulcerative colitis, and 3 with IBD unclassified. The median age at diagnosis (IQR) was 11.8 years (9.6, 13.4) and 13.7 years (10.1, 14.75) at the time of initially commencing anti-TNF. Twenty-five (76%) patients were prescribed co immunosuppression with azathioprine (n¼20) and methotrexate (n¼5). No patients were receiving steroid therapy at the time of switching. The median time on infliximab before switching was 1.6 years (IQR 1.5, 2.1). At the time of switching 25 patients (76%) were classified as remission and 8 had active disease (5 mild, 2 moderate, 1 severe)

Intervention Biosimilar infliximab

Comparateur originator infliximab


Principal Clinical disease activity indices, namely the weighted Paediatric Crohn Disease Activity Index (10) and Paediatric Ulcerative Colitis Activity Index were used to document disease activity

Secondaires erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), albumin, faecal calprotectin, infliximab trough level, and antibody status were also collected for analysis

Milieu de dispensation des soins Scottish regional services

Durée du suivi 6 and 12 months post-switch


Puissance

Type Where median values are quoted, range is given as an interquartile range (IQR).

Test Statistics were calculated using Microsoft excel and SPSS software. P values were limited to patients who had data collected at all 3 time points.

Conclusion générale des auteurs In summary, switching from originator infliximab to the biosimilar appears not to be associated with any increase in infusion reactions or significant loss of effectiveness in the short term in PIBD and is acceptable for the patients.

Financement de l’étude The work of the IBD team in Glasgow is supported by the Catherine McEwen foundation. R.K.R. is supported by an NHS senior research fellowship. R.H. and P.H. are funded by a career researcher fellowship from NHS Research Scotland. The work of the IBD team in Edinburgh is supported by the Edinburgh Children’s Hospital Charity.

Déclaration des conflits d’intérêts L.G. has received conference fees from Tillots May 2017 and V.G. from Abbvie 2017. R.T. was the speaker and received conference fees from Nutricia. R.H. received conference support, speaker’s fees, and consultancy fees from Nutricia, MSD Immunology, Dr Falk, and 4D Pharma. D.C.W. received consultancy, speaker fees, and meeting expenses from Abbvie; consultancy from Takeda; and speaker fee from Falk. R.K.R. was supported/contracted by Research for Nestle Health Sciences plus Consulting Fees for Abbvie, Therakos, Celltrion, and Vifor. The remaining authors report no conflicts of interest.

Approbation éthique Specific ethical approval was not required for this review of clinical practice.


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Tableau D23 – Caractéristiques de Glintborg 2019

Auteur, année Glintborg et ses collaborateurs, 2019

Essai clinique

Nom (no) N.D.

Phase N.D.


N.D.

Titre To switch or not to switch: Results of a nationwide guideline of mandatory switching from originator to biosimilar etanercept. One-year treatment outcomes in 2061 patients with inflammatory arthritis from the DANBIO registry

Objectif Real-world evidence on effectiveness of switching to biosimilar etanercept is scarce. In Denmark, a nationwide guideline of mandatory switch from 50 mg originator (ETA) to biosimilar (SB4) etanercept was issued for patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA) in 2016. Clinical characteristics and treatment outcomes were studied in ETA-treated patients, who switched to SB4 (switchers) or maintained ETA (non-switchers). Retention rates were compared with that of a historic cohort of ETA-treated patients. Switchers who resumed ETA treatment (back switchers) were characterised.

Devis et méthode ECRNA comparé à une cohorte historique 1 April 2016 and 1 January 2017.


N= 2061 BR/BS n= 1621 BR/BR n= 440 RA, N=1219 PsA, N=407 AxSpA, n=435

Critères inclusion

Patients with RA, PsA and AxSpA treated with ETA by 1 April 2016

Critères exclusion

N.D.


Intervention BR/BS switched from originator etanercept (ETA) to biosimilar etanercept (SB4)

Comparateur BR/BR etanercept (ETA) BR cohort historic

Principal disease activity Disease flare

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Retention rate

Secondaires N.D.

Milieu de dispensation des soins Eighteen of 23 departments of rheumatology in Denmark

Durée du suivi Median follow-up switchers: 383 (314–414) days, non-switchers: 483 (222–483) days.


Puissance N.D.

Type N.D.

Test Descriptive data are presented by medians (IQR) or as numbers (percentages) for discrete data. Non-parametric statistics were used for comparisons of patient characteristics (Χ2 or Mann- Whitney tests as appropriate). Unless otherwise stated, analyses were based on available data with no imputation of missing data. In switchers, disease activity 3 months before switch (pre switch), at the time of switch, after 3 months (post switch) and changes over time (Δpre switch and Δpost switch) were calculated in each patient. Predefined time windows were applied for measures of disease activity. Missing data at the 3 months’ visit was imputed with the 6 months’ visit. For patients who withdrew ≤3 months post-switch (n=105), data from the latest registered visit after baseline were carried forward. Disease flare in patients with RA and PsA was defined as (1) changes in 28-joint Disease Activity Score (DAS28) ≥0.6 and (2) ΔDAS28 ≥1.2. In AxSpA, Δ(Ankylosing Spondylitis)ASAS Disease Activity Score (ASDAS) ≥1.1 was considered a flare. Remission was defined as DAS28 < 2.6 and ASDAS < 1.3, respectively. Retention rate was the proportion of patients who maintained the same drug in a given time period. Retention rates (=drug survival) in switchers, non-switchers, and the historic cohort was explored with Kaplan-Meier plots and log rank tests. Multiple Cox proportional hazards regression analyses and HRs stratified by indication (RA/PsA/AxSpA) were conducted to estimate withdrawal rates adjusted for clinically relevant baseline variables. Comparisons were performed as two sets of analyses: switchers versus the historic cohort and switchers versus non-switchers. The following baseline variables were included: age, gender, methotrexate (MTX) (yes/no), comorbidities (0/≥1), remission (yes/no) and ETA start year (1998–2010/2011–2016). Similarly, adjusted 1-year retention rates with 95% CI were calculated. In the comparison of switchers versus the historic cohort, robust variance calculation was applied to account for repeated subjects with left truncation of events (1 January 2015), and all observations were censored after 1 year. Baseline data were complete for all covariates except remission status, which was available in 79% of switchers, 92% of non-switchers and 91% of patients in the historic cohort. Since remission status was closely associated with patient’s global score (PGS), additional multiple Cox regression analyses were performed for sensitivity, in which remission status (yes/no) was replaced by PGS (categorical: ≤30 mm/>30 mm).


In conclusion, we found that a nationwide switch from originator to biosimilar ETA in 1621 patients with inflammatory arthritis had no negative impact on 3 months’ disease activities, and no major safety events were observed. Despite mandatory switch recommendations, one in five ETA-treated patients did not switch. In both patient groups, withdrawal was most common in patients not in remission. These real-world data indicate that switch outcomes in routine care are affected by non-specific drug effects and patient-related factors.

Financement de l’étude The study was partly funded by a grant from Biogen, who had no influence on the study design, analyses, interpretation or the decision to publish the results.


BG: AbbVie, Biogen, Pfizer, MSD. MLH: Orion, BMS, AbbVie, Biogen, Pfizer, MSD, Celltrion. IMJH: Roche. AGL: AbbVie, MSD, Novartis, Pfizer, Roche, UCB OH: AbbVie, Roche, Novartis. HN: AbbVie, Novartis, Medac. LSA: Pfizer. The remaining authors: none declared.

Approbation éthique Observational registry.


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Tableau D24 – Caractéristiques de Glintborg 2017


Essai clinique

Nom (no) N.D.

Phase N.D.


N.D.

Titre A nationwide non-medical switch from originator infliximab to biosimilar CT-P13 in 802 patients with inflammatory arthritis: 1-year clinical outcomes from the DANBIO registry

Objectif According to guidelines, a nationwide non-medical switch from originator (INX, Remicade®) to biosimilar infliximab (Remsima®, CT-P13) was conducted in Danish patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondylarthritis (AxSpA). We investigated disease activity before/after switching and retention rates in the DANBIO registry.

Devis et méthode ECRNA comparé à une cohorte historique


N= 802 BR/BS n= 802

Critères inclusion

Patients with inflammatory arthritis in DANBIO who had been followed since start of first bDMARD and who switched from INX to CT-P13 before 1 January 2016 were included (table 1). In addition, 28 patients from two hospitals, where the switch guideline was adapted later, were included.

Critères exclusion

N.D.


Intervention BR/BS (Remicade® [REM]) to a biosimilar infliximab (CT-P13 [Remsima®; Inflectra]).

Comparateur Historical cohort BR Remicade® (nombre inconnu)


Principal Disease activity Disease flare Treatment retention

Secondaires N.D.

Milieu de dispensation des soins All departments of rheumatology in Denmark

Durée du suivi Follow-up was 413 (339–442) days.


Puissance N.D.

Type N.D.

Test Statistical analyses were performed by SPSS 22 and SAS 9.4. Descriptive data are presented by medians (IQR). Non-parametric statistics were used for comparisons. p Values < 0.05 were considered statistically significant. Disease activity 3 months before switch (pre switch), at the time of switch, after 3 months (post switch) and changes over time (Δ pre switch and Δ post switch) were calculated in each patient. Missing data at the 3 months’ visit were imputed with the 6 months’ visit. For patients who withdrew ≤3 months post switch (n=18), data from the latest registered visit after baseline were carried forward.

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Disease flare was defined as changes in 28 Joint Disease Activity Score (DAS28) ≥0.6 or ΔDAS28 ≥1.2 (rheumatoid arthritis (RA), psoriatic arthritis (PsA)), and Δ Ankylosing Spondylitis Disease Activity Score (ASDAS) ≥1.3 (axial spondyloarthritis (AxSpA)). Remission was defined as DAS28 < 2.6 and ASDAS < 1.3, respectively. Treatment retention among switchers was explored with Kaplan-Meier plots and log-rank tests. Univariable and multivariable Cox regression analyses and HR stratified by diagnosis (RA/PsA/AxSpA) were used to identify baseline predictors of CT-P13 retention (gender/age/methotrexate(yes–no)/CT-P13 dose/CT-P13 interval/comorbidities (number) and baseline disease activity (patient’s global score/Bath Ankylosing Spondylitis Disease Activity Index score/ASDAS/DAS28)). Age and gender were forced into the model. Variables with p<0.1 on univariate analysis were included in the multivariate model (stepwise backwards selection). The 1-year treatment retention was compared with that of a cohort of all patients in DANBIO receiving treatment with INX by 1 January 2014. Cox proportional hazards regression analysis was used to compare the crude 1-year retention rate in the two groups with a robust variance calculation implemented to account for repeated subjects. Multivariable Cox regression analysis with left truncation (1 January 2014) and years since start of INX as timescale was performed to calculate HR for withdrawal adjusted for the following baseline variables — age/ gender/diagnosis/methotrexate(yes–no)/comorbidities(number)/ patient’s global score — and to calculate adjusted 1-year retention rates for INX and CT-P13.


In conclusion, a nationwide non-medical switch from INX to CT-P13 in 802 patients with inflammatory arthritis, who had previously been treated with INX for > 6 years, had no apparent negative impact on disease activity. The adjusted retention rate during ≈1 year of follow-up was slightly reduced (3.4%) compared with a historic cohort.

Financement de l’étude The study was funded in part by a research grant from AbbVie.


BG: AbbVie; IMJH: Roche; AGL, MLH: AbbVie, BMS, MSD, Pfizer, Roche and UCB; the remaining authors: none declared.

Approbation éthique According to Danish legislation, registration and publication of data from clinical registries do not require patient consent or approval by ethics committees.


Tableau D25 – Caractéristiques de Goll 2019

Auteur, année Goll et ses collaborateurs, 2019

Essai clinique Nom (no) NCT-02148640 : Open-label extension of the NOR-SWITCH trial EudraCT Number: 2014-002056-40

Phase Phase IV extension


N.D.

Titre Long-term efficacy and safety of biosimilar infliximab (CT-P13) after switching from originator infliximab: Open-label extension of the NOR-SWITCH trial

Objectif The NOR-SWITCH extension trial aimed to assess efficacy, safety and immunogenicity in patients on CT-P13 throughout the 78-week study period (maintenance group) versus patients switched to CT-P13 at week 52 (switch group).

Devis et méthode ECRA extension, ENCAA for the switch


N (original) =482 BR/BR = 241 BR/BS = 222 N (Extension) = 380 BR/BR/BS = 183 BR/BS/BS = 197

Critères inclusion

All of the following conditions must apply to the prospective patient at screening prior to receiving study treatment: 1. A clinical diagnosis of either rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn’s disease or chronic plaque psoriasis 2. Male or non-pregnant, non-nursing female 3. > 18 years of age at screening 4. Stable treatment of innovator infliximab (Remicade®) during the last 6 months 5. Subject capable of understanding and signing an informed consent form

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6. Provision of written informed consent Patients with a diagnosis of Crohn’s disease (CD), ulcerative colitis (UC), spondyloarthritis (SpA), rheumatoid arthritis (RA), psoriatic arthritis (PsA) or plaque psoriasis (Ps) who had completed the main study period (week 0 to week 52) were recruited to a further 26-week follow-up period.

Critères exclusion

Patients will be excluded from the study if they meet any of the following criteria: 1. Major co-morbidities, such as severe malignancies, severe diabetes mellitus, severe

infections, uncontrollable hypertension, severe cardiovascular disease (NYHA class 3 or 4), severe respiratory diseases and/or other diseases including inflammatory conditions for which infliximab is contra-indicated.

2. Change of major co-medication during the last 2 months prior to randomization:

• RA, SpA and PsA: Initiation of systemic corticosteroids or synthetic DMARDs or other medication which according to the investigator would interfere with the stability of the disease.

• UC and CD: Initiation of systemic corticosteroids or an immunosuppressant or other medication which according to the investigator would interfere with the stability of the disease

• Psoriasis: Initiation of methotrexate, cyclosporine or other medication which according to the investigator would interfere with the stability of the disease

3. Inadequate birth control, pregnancy, and/or breastfeeding. Adequate contraception includes oral, injected or implanted hormonal methods of contraception, placement of an intrauterine device or system, vasectomized partner or sexual abstinence.

4. Psychiatric or mental disorders, alcohol abuse or other substance abuse, language barriers or other factors which makes adherence to the study protocol impossible

5. Change in treatment with innovator infliximab (Remicade®) during the last 6 months due to disease related factors, not including dose/frequency adjustments due to drug concentration measurements

6. For patients with UC and CD: Functional colostomy or ileostomy. Extensive colonic resection with less than 25 cm of the colon left in situ.

No extra exclusion criteria, since the patients were previously selected in the NOR-SWITCH trial


Intervention CT-P13

Comparateur Infliximab


Principal The primary end-point was disease worsening during the 26-week follow-up, defined by worsening in disease-specific composite measures and/or a consensus on disease worsening between investigator and patient leading to major change in treatment (the same as in the main study) [14]. Disease worsening according to disease-specific composite measures was defined as ΔHBI ≥4 and HBI level ≥7 points for CD patients, ΔPMS > 3 and PMS level ≥5 for UC patients, ΔASDAS≥1.1 and ASDAS level > 2.1 for SpA patients, ΔDAS28 of ≥1.2 and DAS28 level > 3.2 for RA and PsA patients, and ΔPASI ≥3 and PASI level ≥5 for Ps patients. Δ indicates change from time of switching (baseline week 52) to the end of the 26-week follow-up period (study end minus baseline).

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Secondaires The secondary end-points (for details, see the main study report [14]) included changes in investigator and patient global assessments (study end (week 78) minus baseline extension study (week 52)), changes in erythrocyte sedimentation rate (ESR) as well as C-reactive protein (CRP), overall remission status based on the main composite measures, and study drug discontinuation. Prespecified secondary endpoints for CD and UC were change and remission status of HBI and PMS, respectively, as well as changes in faecal calprotectin levels. In SpA, change in ASDAS and achievement of ASDAS inactive disease were prespecified. Secondary endpoints for RA and PsA included achievement of remission according to DAS28, Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) as well as ACR/EULAR remission criteria. Other secondary endpoints were changes in DAS28, CDAI and SDAI. In Ps, we prespecified the following as secondary endpoints: PASI complete clearance, mild-to-moderate disease, remission and change in PASI score.

Milieu de dispensation des soins Hospital setting: 25 Norwegian hospitals recruited patients to the study.

Durée du suivi 26 weeks, total 78 weeks


Puissance The study was inadequately powered to detect noninferiority within individual diseases.

Type The endpoints of this trial were primarily addressed in the per-protocol set (PPS) and secondarily in the full analysis set (FAS). The PPS population consisted of subjects without major protocol deviations throughout the extension study, whilst the FAS population comprised all subjects entering the extension study.

Test Analysis of the primary endpoint (as well as other binary outcomes) was performed using logistic regression, with intervention group (switch versus maintenance) as a covariate. Continuous outcomes were analysed using linear mixed-effect models, treating time as a categorical variable and including a time-by-treatment group interaction. Severely skewed variables, such as CRP, were log-transformed prior to model estimation. Analyses of both binary and continuous outcomes were adjusted for diagnosis and duration of infliximab use at the time of switch (baseline extension study, week 52).

Conclusion générale des auteurs The extension of the NOR-SWITCH study supports that switching from originator to CT-P13 does not have a negative impact on efficacy, safety and immunogenicity. These results can be expected to enhance confidence in the use of biosimilars in patients with rheumatic diseases, IBD and psoriasis

Financement de l’étude This trial was supported by a direct grant from the Norwegian government, by the Ministry of Health and Care Services.

Déclaration des conflits d’intérêts GLG reports personal fees from AbbVie, Biogen, Eli Lilly, MSD, Novartis, Pfizer, Roche, Sandoz, Orion Pharma, Celltrion and Boehringer Ingelheim. KKJ reports personal fees from Tillott, Intercept and Celltrion. NB reports personal fees received from Orion Pharma, Roche, Napp Pharmaceuticals, Pfizer and Takeda. ICO reports grants from Norwegian Ministry of Health and Care Services during the conduct of the study and personal fees from Pfizer. EAH reports grants from AbbVie, Pfizer, UCB, Roche and MSD. IPB reports personal fees from AbbVie, MSD, Takeda, Hospira and Ferring. KEAL reports grants from MSD and personal fees from Takeda, Orion, AbbVie, Pfizer and MSD. KST reports personal fees and nonfinancial support from AbbVie, Orion, Novartis, Janssen, Celgene, Mundipharma, Pfizer, MSD and Shire and nonfinancial support from CSL Behring. CM reports personal fees from Novartis Norge AS, LEO Pharma AS, ACO Hud Norge AS, Celgene AS, AbbVie and Galderma Nordic AB. JJ reports personal fees from MSD, AbbVie, Celltrion, Orion Pharma, Takeda, Napp Pharm, Astro- Pharma, Hikma and Pfizer. TKK reports grant from Norwegian Ministry of Health and Care Services during the conduct of the study and personal fees from AbbVie, Biogen, BMS, Boehringer Ingelheim, Celltrion, Eli Lilly, Epirus, Janssen, Merck-Serono, MSD, Mundipharma, Novartis, Oktal, Orion Pharma, Hospira/Pfizer, Roche, Sandoz and UCB Pharma.

Approbation éthique The study was conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. The study protocol and patient consent documents were approved by an independent ethics committee (Regional Committees for Medical and Health Research Ethics South East; reference number 2014/848), by appropriate institutional review boards andby the Norwegian Medicines Agency (reference number 14/07192-11).


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Tableau D26 – Caractéristiques de Griffiths 2017

Auteur, année Griffiths et ses collaborateurs, 2017

Essai clinique

Nom (no) EGALITY study; NCT01891864

Phase 3


N.D.

Titre The EGALITY study: A confirmatory, randomized, double-blind study comparing the efficacy, safety and immunogenicity of GP2015, a proposed etanercept biosimilar, vs. the originator product in patients with moderate-to-severe chronic plaque-type psoriasis

Objectif To demonstrate equivalent efficacy, and comparable safety and immunogenicity of GP2015 and the etanercept originator (ETN, Enbrel®) in patients with moderate-to-severe chronic plaque-type psoriasis.

Devis et méthode ECRA; randomized, double-blind


N= 531 BS n= 264; week 12 BS/BS n= 152 BS/BR/BS/BR n= 100 BR n= 267; week 12 BR/BR n=151 BR/BS/BR/BS n=96

Critères inclusion

men or women ≥ 18 years of age, with active but clinically stable chronic plaque-type psoriasis diagnosed ≥ 6 months before baseline, who had previously received phototherapy or systemic psoriasis therapy at least once or who were candidates for such therapies in the opinion of the investigator. Moderate-to-severe psoriasis at baseline was defined as a Psoriasis Area and Severity Index (PASI) score ≥ 10, an Investigator’s Global Assessment modified 2011 (IGA mod 2011) score ≥ 3 (based on a scale of 0–4) and ≥ 10% body surface area affected by plaque-type psoriasis.

Critères exclusion

any previous exposure to etanercept; exposure to TNF antagonists or other biological immunomodulating agents in the 6 months prior to randomization; ongoing use of prohibited psoriasis treatments such as topical corticosteroids or ultraviolet therapy, or prohibited non psoriasis treatments (all other prior non psoriasis concomitant treatments had to be on a stable dose for ≥ 4 weeks before baseline); presence of active systemic infections in the 2 weeks prior to baseline; or latent tuberculosis detected by imaging or positive QuantiFERON TB Gold test


80


Intervention BR/BS switched from originator Enbrel ® Etanercept to biosimilar GP2015 Etanercept Solution for subcutaneous injection in pre-filled syringe. The drug is administered in a dose of 50 mg twice weekly for the first 12 weeks and 50 mg once weekly thereafter

Comparateur BR/BR Enbrel ® Etanercept


Principal Efficacity

Secondaires Safety

Milieu de dispensation des soins 74 centres in 11 European countries and South Africa

Durée du suivi 52 weeks; June 2013 to March 2015


Puissance A sample size of approximately 546 patients to maintain 464 evaluable patients with an assumed dropout and major protocol deviation rate of 15% was planned to provide a power of 90% to show therapeutic equivalence between GP2015 and ETN.

Type intent-to-treat

Test Based on the statistical hypothesis, therapeutic equivalence in terms of PASI 75 was to be established if the 95% confidence interval (CI) for the difference in the PASI 75 response rates was contained within the prespecified margin range (-18 to 18%). Based on an observed effect size of 45–46% in former placebo-controlled ETN (Enbrel®) studies,3,13 an equivalence margin of 18% was chosen, so that ≥ 60% of the treatment effect had to be maintained. Primary analysis was performed using a logistic regression model that included treatment groups (GP2015 or ETN), body weight categories and prior systemic therapy as stratification factors in the model. The stratification-factor-adjusted treatment differences between GP2015 and ETN, as well as the corresponding 95% CIs, were derived from the regression model. The primary efficacy analysis was

81


based on the per protocol set (PPS), which consisted of all patients who completed the study until week 12 without major protocol deviations. Dropouts due to unsatisfactory therapeutic effect were included in the PPS as non responders provided, they received at least 4 weeks of treatment. The analysis was repeated on the full analysis set (FAS) following the intent-to-treat principle as a sensitivity analysis. The main secondary efficacy variable was analysed using a powered mixed-model repeated-measures approach14 and an averaged treatment effect approach using an ANCOVA model. No imputation for missing PASI scores or components of PASI scores was performed. Both approaches had a prespecified margin range (-15 to 15%) to claim therapeutic equivalence and were performed on the PPS and repeated on the FAS. A smaller equivalence margin than for the primary analysis was chosen because of a lower effect size for the more sensitive variable percentage change from baseline in PASI score.


In conclusion, the efficacy of GP2015 was equivalent to that of ETN in patients with moderate-to-severe chronic plaque-type psoriasis. There were no clinically meaningful differences in efficacy, safety or immunogenicity between GP2015 and ETN up to 52 weeks of treatment. No new or unexpected safety issues were reported, and the safety profiles of GP2015 and ETN were similar to those observed in previous ETN studies. Switching treatments did not impact efficacy, safety or immunogenicity. The study results provide clinical confirmation of biosimilarity and contribute to the totality of the evidence proposing GP2015 as an etanercept biosimilar.

Financement de l’étude The study was funded by Hexal AG, a Sandoz company. The funder had a role in the study design, data collection, data analysis and manuscript preparation.


C.E.M.G. has received consultancy/ honoraria and/or research funding from AbbVie, BMS, Galderma, Janssen, LEO Pharma, Lilly, MSD, Novartis, Pfizer, Regeneron, Roche, Sandoz and UCB Pharma. D.T. has received research support from AbbVie, Almirall, Amgen, Astellas, Biogen Idec, Boehringer Ingelheim, Celgene, Dignity, Eli Lilly, Forward Pharma, GlaxoSmithKline, LEO Pharma, Janssen-Cilag, Maruho, MSD, Mitsubishi Pharma, Novartis, Pfizer, Roche and Sandoz; and honoraria from AbbVie, Biogen Idec, Celgene, Janssen, LEO Pharma, Mundipharma, Novartis, Pfizer and Roche-Possay; and has acted as a consultant for AbbVie, Biogen Idec, Celgene, Dignity, Galapagos, Maruho, Mitsubishi, Novartis, Pfizer and Xenoport and sat on scientific advisory boards for AbbVie, Amgen, Biogen Idec, Celgene, Eli Lilly, GlaxoSmithKline, Janssen, LEO Pharma, Mundipharma, Novartis, Pfizer and Sandoz. S.G. has been an advisor and/or received speakers’ honoraria and/or received grants and/or participated in clinical trials for the following companies: Abbott/AbbVie, Almirall-Hermal, Amgen, Bayer Health Care, Biogen Idec, Bioskin, Boehringer Ingelheim, Celgene, Centocor, Dermira, Eli Lilly, Foamix, Forward Pharma, Galderma, Hexal AG, Isotechnika, Janssen-Cilag, LEO Pharma, Medac, Merck Serono, Mitsubishi Tanabe, MSD, Novartis, Pfizer, Sandoz Biopharmaceuticals, Schering-Plough, Takeda, Teva, UCB Pharma, VBL Therapeutics and Wyeth Pharma. P.A. has received grants from Novartis. G.P. has served as a principal investigator in clinical studies sponsored by Almirall, Amgen, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Merck, MSD, Novartis, Regeneron, Roche, Sandoz, Sanofi Aventis and Takeda. K.K. has served as a principal investigator in clinical studies sponsored by Celgene, Mitsubishi Pharma, Merck, Novartis, Regeneron and Sandoz. J.W. has served as an investigator and speaker for Amgen, Eli Lilly, Galderma, Janssen- Cilag, LEO Pharma, Maruho, Mitsubishi Pharma, Novartis, Pfizer, Roche, Regeneron and UCB Pharma. N.H., J.P., H.W., G.W. and M.A. are employees of Hexal AG.

Approbation éthique This study was conducted in accordance with the ethical principles derived from the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practices and in compliance with local regulatory requirements and was reviewed and approved by the independent ethics committee or institutional review board for each centre. All patients provided written informed consent before entering the study.


Tableau D27 – Caractéristiques de Guerra Veloz 2019

Auteur, année Guerra Veloz et ses collaborateurs, 2019


Phase N.D.


N.D.

Titre Long-term follow up after switching from original infliximab to an infliximab biosimilar: real-world data

82


Objectif Here, we assessed the long-term efficacy data, loss of response and safety after switching from infliximab to CT-P13 in patients with inflammatory bowel disease.

Devis et méthode This was a prospective observational study


100 patients with IBD (64 with CD and 36 with UC) were included.

Critères inclusion

The cohort included all patients with a previous diagnosis of moderate-to-severe CD or UC, whose treatment was switched from original IFX (Remicade®) to CT-P13 in March 2015 and had completed 24 months of follow up.

Critères exclusion

N.D.


Intervention CT-P13



Principal The primary endpoint was to analyze the loss of response to IFX after switching.

Secondaires The secondary endpoints were: - To analyze safety during 24 months of follow up. - To compare changes in biochemical markers such as C-reactive protein (CRP) at 0, 12, 18 and 24 months. - To compare IFX trough levels at 12, 18 and 24 months after switching medications.

Milieu de dispensation des soins Virgen Macarena University Hospital (Seville, Spain)



Puissance N.D.

Type Demographic and nominal results were reported in percentages and frequencies. Numerical results were reported as the mean and standard deviation in cases of normal distribution, and as the median and interquartile range (IQR) in cases of skewed distribution.

83


Test The Cochrane’s Q test and the Friedman test were used to analyze the evolution of the clinical scores (HB index and partial Mayo score), the CRP values and the IFX serum drug levels. Confidence intervals (CIs) were calculated at 95% and a p value of 0.05 was used as the statistical significance level

Conclusion générale des auteurs Despite the already discussed limitations, this study provides valuable data regarding the long term efficacy of CT-P13 treatment after switching from the original IFX and demonstrates that most of the patients maintained the therapy with a good profile of efficacy and safety after 2 years of follow up.

Financement de l’étude The authors received no financial support for the research, authorship, and/or publication of this article.

Déclaration des conflits d’intérêts M.F. Guerra Veloz, M. Belvis Jiménez, T. Valdez Delgado, L. Castro Laria, B. Maldonado Pérez have received financial support from Kern Pharma to attend scientific meetings. F. Argüelles-Arias has participated in advisory boards and has received financial support from Kern Pharma to attend scientific meetings. R. Perea Amarillo, V. Merino Bohórquez, A. Caunedo Álvarez and A. Vilches Arenas declare that there is no conflict of interest

Approbation éthique The study was approved by the Research Ethics Committee of Virgen Macarena University Hospital, Seville, Spain (SAP-INF-2015).


Tableau D28 – Caractéristiques de Guerra Veloz (B) 2018



Phase N.D.


N.D.

Titre Switching from reference infliximab to CT-P13 in patients with inflammatory bowel disease: Results of a multicenter study after 12 months

Objectif The objective of the study was to assess the effectiveness and safety of switching from the reference product (RP), infliximab, to CT-P13 in patients with IBD.

Devis et méthode This was a multicenter observational study, ENCAA


BR/BS n = 167

Critères inclusion

Patients with CD or UC who had previously been treated with infliximab RP were included in the study

Critères exclusion

N.D.


Intervention CT-P13

Comparateur Infliximab RP (Remicade®)

84



Principal The efficacy endpoint was the change in clinical remission in patients who switched from infliximab RP to CT-P13 which was assessed at 12 months. With regard to patients with CD and UC in remission at the time of switching, remission was considered if the patient remained in clinical remission (HB score ≤ 4 in patients with CD or partial Mayo score ≤ 2 in patients with UC) without the need for steroids, surgery or an increased dose at the established follow-up time. In patients with CD and UC who were not in remission at the time of the drug switch, remission was considered if patients achieved a HB score ≤ 4 for CD and a partial Mayo score ≤ 2 for UC. The value of the HB score, the partial Mayo score and the C-reactive protein (CRP) at the drug switch time was compared with their respective value after 12-months of follow-up.

Secondaires Adverse events (AE) were monitored from the first infusion of CT-P13 until the end of the study and were recorded according to the Office of Human Research Protection (31).

Milieu de dispensation des soins Hospital Virgen Macarena and Hospital Juan Ramon Jiménez (Seville-Huelva, Spain)



Puissance N.D.

Type Demographic and nominal results were reported as percentages and frequencies. Numerical results were reported as an average and standard deviation in cases of a normal distribution and as a median and interquartile range in the cases of a skewed distribution

Test The Wilcoxon test was used to compare the clinical scores (HB score and partial Mayo score) and CRP values of patients; 95% confidence intervals (CI) were calculated and α was set at 0.05 for the determination of statistical significance.

Conclusion générale des auteurs In conclusion, this study provides valuable data on the long-term efficacy of CT-P13 maintenance treatment after switching from infliximab RP. Our results have demonstrated a good clinical efficacy and safety at 12 months in real life clinical practice. The loss of efficacy at 12 months was 15.7%, similarly to that reported for the reference product, infliximab.


Déclaration des conflits d’intérêts MF Guerra Veloz, JM Vázquez Morón, M Belvis Jiménez, H Pallarés Manrique, T Valdés Delgado, L Castro Laria, B Maldonado Pérez, A Benítez Roldán and A Caunedo Álvarez do not have conflicts of interest. F Argüelles-Arias has participated in advisory boards and has received financial support to attend scientific meetings from Kern Pharma.

Approbation éthique The study was approved by the Research Ethics Committee of the Hospital Virgen Macarena and Hospital Juan Ramon Jiménez


Tableau D29 – Caractéristiques de Guerra Veloz 2018 (A)



Phase N.D.


N.D.

Titre Loss of efficacy and safety of the switch from infliximab original to infliximab biosimilar (CT-P13) in patients with inflammatory bowel disease

Objectif To compare the efficacy of infliximab biosimilar, CT-P13, against infliximab original, analyzing the loss of response of both at the 12-mo follow-up in patients with IBD.

Devis et méthode An observational study of two cohorts


196

Critères inclusion

In the retrospective cohort we included all the patients with CD or UC who were treated with infliximab original at least once in 2014. In the prospective cohort we included all the patients with CD or UC who had been switching from infliximab original to infliximab biosimilar and had completed a 12 month follow-up.

Critères exclusion

N.D.

85



Intervention CT-P13

Comparateur infliximab RP


Principal The efficacy endpoint was the change in clinical remission in patients with infliximab original, and in patients switched from infliximab RP to CT-P13 assessed at 12 mo.

Secondaires Adverse events (AE) were monitored from the first infusion of CT-P13 until the end of the study and they were recorded according to the Office of Human Research Protection.

Milieu de dispensation des soins Virgen Macarena Hospital (Seville, Spain).



Puissance N.D.

Type Demographic and nominal results were reported in percentages and frequencies. Numerical results were reported as average and standard deviation in cases of normal distribution and as median and interquartile range (IQR) in cases of asymmetrical distribution.

Test The Wilcoxon test was used to compare the clinical scores (HB Score and partial Mayo Score) and the CRP values of patients. McNemar’s test and the Cochran Q test were used to compare both groups’ remission. 95% confidence intervals (CIs) were calculated and α was set at 0.05 for the determination of statistical significance.

Conclusion générale des auteurs We conclude that the overall efficacy and loss of treatment response with Infliximab biosimilar (CT-P13) is similar to that observed with Infliximab original in patients who were switching at the 12 mo follow-up.


Déclaration des conflits d’intérêts Guerra Veloz MF, Castro Laria L, Maldonado Pérez B, Perea Amarillo R and Argüelles-Arias F have received financial support to attend scientific meetings from Kern Pharma. Benítez Roldán A, Merino Bohórquez V, Calleja MA, Caunedo Álvarez Á, and Vilches Arenas Á do not have conflict of interest.

Approbation éthique The study was approved by the Research Ethics Committee of the Virgen Macarena Hospital.


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Tableau D30 – Caractéristiques de Guerrero Puente 2017

Auteur, année Guerrero Puente et ses collaborateurs, 2017


Phase N.D.


N.D.

Titre Evolution after switching to biosimilar infliximab in inflammatory bowel disease patients in clinical remission

Objectif The aim of this study was to assess the efficacy, safety, bioavailability profile and factors associated with relapse after switching to biosimilar infliximab in IBD patients in clinical remission.

Devis et méthode This was an observational, retrospective and single-centre study comprising a single cohort of patients with Crohn’s disease (CD) and ulcerative colitis (UC)


36 patients with IBD (13 with UC, 23 with CD)

Critères inclusion

Patients who had received at least six months of maintenance therapy with the reference product (Remicade®) and who were in corticosteroid-free clinical remission for at least three months were enrolled.

Critères exclusion

Patients under the age of 18 years and patients treated with reference infliximab for an indication other than IBD were excluded.


Intervention Biosimilar infliximab (Remsima®)

Comparateur Reference infliximab (Remicade®)


Principal The primary endpoint was relapse or loss of response to treatment after switching, defined as increased activity as assessed by the clinic, as well as laboratory, radiology and endoscopy findings, which led to a change in the patient’s treatment in order to control his/her disease

Secondaires Levels of infliximab and ATI (antibodies to infliximab) were measured in all patients before administering each infusion of Remicade® and the biosimilar CT-P13 after switching. The safety data recorded at each infusion and during the period preceding the next dose of the drug were collected.

Milieu de dispensation des soins Hospital Reina Sofía in Córdoba

Durée du suivi The mean duration of patient follow-up was 8.4 months (± 3.5).


Puissance N.D.

Type The variables were presented in frequency tables or expressed as means and standard deviation, except those variables with asymmetrical distribution, for which the median and interquartile range were used.

87

Auteur, année Guerrero Puente et ses collaborateurs, 2017

Test The chi-square test (or Fisher’s exact test when necessary) was used for the frequencies, Student’s t test or ANOVA for the quantitative variables and the Mann---Whitney U test or Kruskal---Wallis test for asymmetrical distributions. The Kaplan-Meier method was used to estimate the impact of switching to biosimilar CT-P13 on relapse-free survival, while the log-rank test was used to compare the curves. Finally, a multivariate Cox regression analysis was performed to evaluate the impact of the various prognostic factors on relapse-free survival after switching. A p < 0.05 was considered significant. The larger Cox model comprised those variables with p < 0.25. Clinically significant variables identified in prior studies irrespective of their significance in the univariate analysis were also included. Covariates were removed from the larger Cox model by means of a step-by-step process, eliminating those variables with a p > 0.15 one by one, starting with the variables with the highest p-value. The remaining covariates formed the smaller Cox model. The variables with a p-value between 0.05 and 0.15 were selected to identify potential confounding factors and were removed from the model if they did not behave as such.

Conclusion générale des auteurs In conclusion, switching to biosimilar infliximab in a real-life cohort of patients with IBD in clinical remission does not seem to have a significant impact on short-term clinical outcomes. The factors associated with relapse were similar to those expected during follow-up in patients who continued with the reference product.


Déclaration des conflits d’intérêts The authors declare that they have no conflicts of interest.

Approbation éthique The study was conducted in accordance with international ethical guidelines for research and clinical studies in humans established in the Declaration of Helsinki of 1964 and its subsequent updates, and with the recommendations of the Spanish Ministry of Health concerning clinical studies. The study protocol was approved by the Independent Ethics Committee of Córdoba.


Tableau D31 – Caractéristiques de Guiotto 2019

Auteur, année Guiotto et ses collaborateurs, 2019


Phase N.D.


N.D.

Titre Switching from infliximab originator to a first biosimilar is safe and effective. Results of a case-control study with drug levels and antibodies evaluation

Objectif To explore safety and effectiveness of switching from the infliximab originator to a first biosimilar.

Devis et méthode Prospective observational study: Data were retrospectively collected from clinical records


66 patients enrolled in the study, including 53 in the switched group and 13 in the naïve group

Critères inclusion

Naïve group: IBD patients whose infliximab treatment started, and continued, with CT-P13 (Remsima®), according to prescribing indications and practice guidelines Switched group: IBD patients who were initially treated with infliximab originator (Remicade®) and who were scheduled to undergo a therapeutic switch to CT-P13 (Remsima®) after April 2016.

Critères exclusion

N.D.

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Auteur, année Guiotto et ses collaborateurs, 2019


Intervention CT-P13 (Remsima®)

Comparateur Infliximab originator (Remicade®)


Principal Analysis of trough levels and antidrug antibodies (ADAs)

Secondaires Clinical characteristics and treatment outcomes were collected and aligned at all observation time point.

Milieu de dispensation des soins Gastroenterology Unit, Mauriziano Hospital, Turin, Italy



Puissance Sample size assumption was based on non-inferiority or superiority, setting as the major clinical outcome the proportion of patients remaining in treatment (75%). With a delta margin of non-inferiority or superiority of 0.10, and with beta power of 0.90 and alpha error of 0.05, the minimal required sample size was calculated to be 26 cases

Type Differences in categorical variables (e.g. occurrence of adverse events, discontinuation of treatment)

Test Tested for significance using the chi-square test or Fisher’s exact test. Continuous variables were compared with the Mann–Whitney test. Binary time-dependent analyses, to identify covariates significantly associated with different outcomes, were done with Kaplan–Meier survival analysis. When a cut-off value was needed to transform continuous variables into categorical variables, receiver operating characteristics (ROC) analysis was used to identify the best performing value. Multivariate logistic regression (for categorical outcomes) or Cox proportional hazard regression (for time-dependent multi-variate analysis) were used to test independent associations for multivariate analysis. A p value ≤ 0.05 was considered to indicate significance.

Conclusion générale des auteurs We therefore conclude that switching from infliximab originator to a first biosimilar is safe and effective, and thus ethically acceptable for the purpose of reducing costs of healthcare. In patients with active disease, probably the safest and most effective option is to change the active compound to a different anti-TNF agent or to a drug with a different mechanism of action, while switching to a biosimilar and optimizing the dose is an alternative to be carefully proposed to patients.

Financement de l’étude The study was supported by grants from Fondazione IBD Onlus (Turin, Piedmont, Italy) and Fondazione Scientifica Mauriziana (Turin, Piedmont, Italy) which covered the costs of trough level and antidrug antibody analyses.

Déclaration des conflits d’intérêts None declared.

Approbation éthique approved by local Ethical Committee


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Tableau D32 – Caractéristiques de Haag-Weber 2009

Auteur, année Haag-Weber et ses collaborateurs, 2009


Phase N.D.


N.D.

Titre Therapeutic equivalence, long-term efficacy and safety of HX575 in the treatment of anemia in chronic renal failure patients receiving hemodialysis

Objectif The primary objective of the study was the evaluation of therapeutic equivalence in terms of hemoglobin (Hb) response of HX575 compared with the comparator product (EPREX®/ ERYPO®, Janssen-Cilag/Ortho Bio tech, Neuss, Ger many) in the long-term intravenous (i.v.) treatment of anemia in chronic renal failure patients on hemodialysis following a 1 : 1 dose conversion from the comparator product to HX575.

Devis et méthode Part 1 : ECRA, double-blind, randomized, multicenter, parallel-group equivalence Part 2 : extension


Randomized patients= 479; safety population = 478; HX575 group = 314; Comparator epoetin alpha = 164

Critères inclusion

Clinically stable adults, suffering from renal anemia and receiving dialysis 3 times a week for at least 6 months. The patients were required to have hemoglobin (Hb) values within the established target range of 10.0 – 13.0 g/dl for at least 12 weeks before screening, and to have been treated with a stable (< 25% change) iv. dose of the comparator epoetin-α 3 times weekly (maximum weekly dose: 300 IU/kg) for at least 8 weeks prior to screening and during the 2-week screening/base line period. Only patients with a mean base line Hb concentration within the target range, C-reactive protein < 15 mg/l, serum ferritin ≥ 100 µg/l and/or saturated transferrin levels ≥ 20% were randomized.

Critères exclusion

Patients were excluded if they had received red blood cell (RBC) transfusions within 14 weeks prior to randomization, or if they had hematological, hepatic, immunological, infectious, or other conditions that might have interfered with the erythropoietic response. Concomitant immunosuppressant or androgen medication was not allowed during the study or before the study for 1 and 2 months, respectively


Intervention equivalent dose of HX575 at a 1 : 1 dose conversion

Comparateur Epoetin-α 3 times a week


Principal The primary end point of Part I was the mean absolute change in Hb levels between the screening/baseline and evaluation period.

Secondaires Secondary end points included the course of weekly Hb concentrations, frequency of treatment responders, frequencies of patients with Hb values in the target range and with Hb values continuously ≥10 g/dl, change in epoetin dosage and requirement of RBC transfusions. The safety profile was assessed by the documentation of adverse

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Auteur, année Haag-Weber et ses collaborateurs, 2009

events (AEs), analysis of laboratory parameters, epoetin antibodies and vital signs. Deaths were re corded by the primary investigators, who also made a clinical judgement as to whether they were related to study medication based on the available information.

Milieu de dispensation des soins 56 specialist dialysis centers in Germany and Austria

Durée du suivi Part 1 : 28 weeks; Part II : 56 weeks


Puissance A sample size of 462 patients was determined to ensure 90% power to demonstrate equivalence at a 5% significance level.

Type Therapeutic equivalence of HX575 to the comparator epoetin- was considered to be demonstrated if the 95% confidence interval (CI) of the difference in mean changes in Hb levels between treatment groups lay within the interval of ± 0.5 g/dl.

Test The difference was determined by an analysis of co-variance (ANCOVA) including treatment, center and mean base line Hb (< 11.5 or ≥ 11.5 g/dl) as factors, and the change in the mean weekly epoetin dose from baseline to the evaluation period as covariate. For sensitivity analyses, additional ANCOVA mod elsewhere used, including a sub group analysis of patients with baseline Hb values of 10 – 12 g/dl or 11 – 13 g/dl, or excluding the covariates “change in epoetin dose” and “change in epoetin dose/base line Hb level”.

Conclusion générale des auteurs This study demonstrated efficacy, typical safety profile and therapeutic equivalence of the first biosimilar ESA versus a comparator epoetin-α. The successful development of HX575 further increases choices of and potentially access to ESA therapy.

Financement de l’étude This study was sponsored by Sandoz AG/ Hexal AG, Holzkirchen, Ger many.

Déclaration des conflits d’intérêts Marianne Haag-Weber de clares no conflict of interest, Andrea Vetter and Ursula Thyroff-Friesinger are employed by Sandoz AG.

Approbation éthique The study was approved by the local Ethics Committees


Tableau D33 – Caractéristiques de Hadjiyianni 2016

Auteur, année Hadjiyianni et ses collaborateurs, 2016

Essai clinique

Nom (no) Element-1 : NCT01421147 Element-2 : NCT01421459

Phase 3


N.D.

Titre Efficacy and safety of LY2963016 insulin glargine in patients with type 1 and type 2 diabetes previously treated with insulin glargine

Objectif this paper examines whether any treatment differences exist in clinical outcomes between LY IGlar and IGlar in the prior IGlar subgroups. Such data may be relevant in clinical practice.

Devis et méthode Post hoc analyse de 2 ECRA


N= 750 BR/BS: T1D n= 218, T2D n= 154 BR/BR : T1D n= 234, T2D n= 144

Critères inclusion

Element-1:Inclusion criteria included T1D duration of ≥1-year, age ≥18 years, receiving basal‐bolus insulin therapy for ≥1 year before screening, HbA1c ≤11.0% and body mass index ≤35 kg/m2. Element-2: Eligible study participants had T2D based on World Health Organisation diagnostic criteria 24, were aged ≥18 years, had been receiving ≥2 oral anti hyperglycaemic medications at stable doses for 12 weeks before screening (with or without IGlar), had HbA1c levels ≥7.0 and ≤11.0% if insulin‐naïve or ≤11.0% if previously on IGlar, and had a body mass index ≤45 kg/m2

Critères exclusion

Element-1: treatment with a biosimilar IGlar, oral anti hyperglycaemic medications, recent twice‐daily IGlar treatment, pramlintide, or continuous subcutaneous insulin infusion, total daily insulin dose ≥1.5 U/kg, or ≥1 episode of severe hypoglycaemia or emergency room visit or hospitalization for poor glucose control within the past 6 months. The pre-study basal‐bolus regimen was required to be a once‐daily basal insulin injection

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of NPH, IGlar, or detemir for ≥3 months (≥90 days) before screening, combined with mealtime injections of human regular insulin, insulin analogue lispro, aspart or glulisine. Element-2: Exclusion criteria included treatment with pramlintide (Symlin®) or any other insulin except IGlar within the previous 30 days, treatment with a biosimilar insulin glargine within the previous 90 days, history of receiving basal‐bolus therapy or, in the investigator's opinion, requirement for mealtime insulin to achieve target control, total daily insulin dose ≥1.5 U/kg, and more than one episode of severe hypoglycaemia within the past 6 months.


In both studies, baseline characteristics were generally similar between both groups and consistent with the FAS, except for race in patients with T2D. As expected, patients with T2D who reported prior IGlar had slightly lower baseline HbA1c and FPG than the FAS.

Intervention BR/BS patients transitioned from their pre-study IGlar to equivalent doses of LY IGlar

Comparateur BR/BR patients transitioned from their pre-study IGlar to equivalent doses of IGlar


Principal Primary efficacy (change in glycated haemoglobin from baseline to 24 weeks)

Secondaires efficacy and select safety outcomes of LY IGlar were compared with those of IGlar.

Milieu de dispensation des soins Element-1: 52 study locations in 9 countries Element-2: 62 locations in 12 countries

Durée du suivi Element-1: 52 weeks, August 2011 to April 2013 Element-2: 28 weeks, September 2011 to September 2012


Puissance N.D.

Type N.D.

Test Post hoc analyses included proportion of patients achieving HbA1c targets, basal insulin dose, prandial insulin dose (ELEMENT-1), percent weight change from baseline (ELEMENT-1), fasting plasma glucose (FPG), prior IGlar insulin antibody levels and documented symptomatic hypoglycaemia. Continuous data (HbA1c change, weight change) were analysed using an analysis of covariance model with treatment, country, time of basal insulin injection, sulphonylurea use (ELEMENT-2 only) as fixed effects and baseline value of response variable as a covariate, and the subgroup (prior IGlar at study entry: yes, no), and subgroup-by-treatment interaction. Treatment comparisons were made within the subgroup of patients who reported pre-study treatment with IGlar. Treatment comparisons for insulin antibody levels and hypoglycaemia rates were carried out using the Wilcoxon test. Hypoglycaemia incidence and the proportion of patients achieving HbA1c targets were analysed using the Mantel-Haenszel test. Categorical data (detectable antibodies, TEAR and AEs) were analysed using Fisher’s exact test.


In conclusion, our results show that patients reporting pre-study IGlar treatment who were randomized to LY IGlar have similar efficacy and safety outcomes to those of patients receiving IGlar. The majority of our findings were consistent with those of the FAS of patients with T1D or T2D [8,9]. Data from these subgroup analyses suggest LY

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IGlar is a well tolerated and effective treatment option when prescribed for patients with T1D and T2D who have had prior treatment with IGlar.



I.H., L. B. L., R.K. P., C. L. C. and L. L. I., are employees of and hold stock in Eli Lilly and Company. D. D. has no conflicts of interest to disclose.

Approbation éthique Methods for both studies, carried out according to ethical principles described in the International Conference on Harmonisation on Good Clinical Practices and Declaration of Helsinki [10], have been reported

Qualité méthodologique Non applicable

Tableau D34 – Caractéristiques de Hercogova 2020

Auteur, année Hercogova et ses collaborateurs, 2020

Essai clinique

Nom (no) AURIEL-PsO; NCT02660580

Phase 3


N.D.

Titre AURIEL-PsO: A randomized, double-blind phase III equivalence trial to demonstrate the clinical similarity of the proposed biosimilar MSB11022 to reference adalimumab in patients with moderate-to-severe chronic plaque-type psoriasis

Objectif To compare the efficacy, safety and immunogenicity of MSB11022 with reference adalimumab.

Devis et méthode ECRA phase III, double-blind, parallel group


N= 443 Core: BR n= 221; BS n= 222 (week 1-16) Extension: BR/BR n= 101; BR/BS n= 101 (weeks 16-52) BS/BS n= 214

Critères inclusion

Sujets adultes présentant une activité modérée à sévère active mais cliniquement stable de psoriasis chronique en plaques diagnostiqué ≥ 6 mois avant étude de base, qui avait déjà reçu une photothérapie ou traitement du psoriasis systémique ou qui étaient candidats à une telle thérapies. Le psoriasis modéré à sévère était défini comme un score de zone de psoriasis et indice de gravité (PASI) ≥12, une évaluation globale du médecin (PGA) modifiée score ≥ 3 (sur une échelle de 0 à 4) et ≥ 10% de la surface corporelle zone affectée par le psoriasis en plaques. Aucune preuve de tuberculose active.

Critères exclusion

Thérapie topique contre le psoriasis ou la photothérapie dans les 2 semaines suivant l'inclusion, et utilisation antérieure de traitement des maladies auto-immunes (autres que l’utilisation de pas plus d'un étanercept ou infliximab)

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Intervention BR/BS switched from Innovator adalimumab to Biosimilar MSB11022 MSB11022 or reference adalimumab was administered at an initial dose of 80 mg subcutaneously, followed by 40 mg every other week starting 1 week after the first dose

Comparateur BR/BR Innovator adalimumab


Principal Efficacity PASI 75 response at week 16

Secondaires Safety, immunogenicity and other efficacity points

Milieu de dispensation des soins 69 centres in North America, South America and Europe

Durée du suivi 68 weeks 16 February 2016 to 18 December 2017


Puissance A sample size of 382 patients was calculated based on two assumptions. Firstly, an estimated response rate of 59% for the primary end point was assumed, based on a weighted mean of response rates observed for various patient populations in previous adalimumab studies

Type intention-to-treat (ITT) and Per protocol

Test The primary efficacy analysis was based on the per protocol set, which consisted of all randomized patients who completed the study until week 16 without major protocol deviations. A sensitivity analysis was performed in the intention-to-treat (ITT) population, which included all randomized patients. Secondary end points were assessed in the per protocol and ITT populations. The safety population included all randomized patients who received a dose of MSB11022 or reference adalimumab. For the primary end point, MSB11022 and reference adalimumab were considered equivalent if the PASI 75 response rate for the MSB11022 arm was within ± 18% of the reference adalimumab arm after 16 weeks of treatment. The two treatment groups were compared using the two-sided 95% stratified Newcombe confidence interval (CI) for the difference in PASI 75 response rate. Therapeutic equivalence was established if the 95% CI was included in the prespecified equivalence interval. Equivalence margins were determined based on values reported in the literature and agreed with the regulatory authorities. Secondly, no

94


expected difference between EU approved reference adalimumab and MSB11022 was assumed following a single 80-mg dose of reference adalimumab at week 1 and a 40-mg dose every other week from weeks 2 to 16. This sample size provided a 90% power for the equivalence margin of 18% and a type I error of 2,5% (one sided). For the per protocol set, little or no missing data were expected, so no imputation was performed. For the ITT analysis, patients with a missing PASI value at week 16 were classified as non responders. The key secondary end point of percentage change in PASI from baseline to week 16 was analysed using an analysis of covariance model, with treatment group and previous systemic therapy use as fixed factors, and baseline PASI as a covariate. Therapeutic equivalence for the key secondary end point was confirmed if the 95% CI of the least squares mean treatment difference was within the predefined interval of ± 15%.


In conclusion, no clinically meaningful differences in efficacy, safety or immunogenicity were seen between MSB11022 and reference adalimumab up to 52 weeks of treatment in a highly sensitive population of patients with moderate-to severe plaque-type psoriasis. No new or unexpected safety issues were reported, and the safety profiles of MSB11022 and reference adalimumab were similar to those reported in previous studies with reference adalimumab. A switch from reference adalimumab to MSB11022 at week 16 did not impact efficacy, safety or immunogenicity. The results presented here provide confirmation of the clinical similarity of MSB11022 and reference adalimumab and contribute to the totality of the evidence supporting MSB11022 as an adalimumab biosimilar.

Financement de l’étude This study was sponsored by Merck. Fresenius Kabi acquired the asset from Merck KGaA in September 2017.


N.D. (pas présent dans appendix comme mentionné)

Approbation éthique All patients provided written informed consent. The study was conducted in accordance with the current International Council on Harmonisation Good Clinical Practice and the Declaration of Helsinki and in compliance with local regulatory requirements. The study protocol was reviewed and approved by the independent ethics committee or institutional review board for each centre.


Tableau D35 – Caractéristiques de Hoivik 2018

Auteur, année Hoivik et ses collaborateurs, 2018


Phase N.D.


N.D.

Titre Switching from originator to biosimilar infliximab – Real world data of a prospective 18 months follow-up of a single-centre IBD population

Objectif We aimed to study the effectiveness, safety and immunogenicity after switching from originator infliximab to CT-P13 in a real-world IBD population with 18 months prospective follow-up.

Devis et méthode Prospective, open-label study


143 IBD patients were switched, 99 with Crohn’s disease (CD) and 44 with ulcerative colitis (UC).

Critères inclusion

all adult (≥18 years) IBD patients treated with originator IFX (Remicade®)

Critères exclusion

N.D.

95

Auteur, année Hoivik et ses collaborateurs, 2018


Intervention CT-P13

Comparateur Infliximab BR


Principal The primary endpoints were (i) the proportion of patients remaining on medication 18 months after switching and (ii) immunogenicity during 18 months after switching.

Secondaires The secondary endpoints included (i) adverse events, (ii) changes in disease activity (HBI and PMS), CRP, Hgb, FC, IFX dose and interval and p-IFX.

Milieu de dispensation des soins Department of Gastroenterology, Oslo University Hospital



Puissance N.D.

Type All continuous data are presented as the median (range or interquartile range (IQR)) or mean (standard deviation (SD)) when appropriate. Categorical data are presented as counts and percentages and compared by using the Chi squared test when appropriate. For the continuous variables CRP, Hgb, FC, p-IFX and mg/kg/week, the change over time after switch was analysed using linear mixed models for repeated measures. Fixed effects of time were estimated, gender and age were included in the analysis as possible confounders. As all measurements were made at equally distributed time points, a diagonal covariance matrix was used to estimate dependencies between measurements.

Test All overall effects were analysed using the F-test. The results are presented as estimated marginal means with 95% confidence intervals (CI). We performed a sensitivity analysis excluding all patients who discontinued the CT-P13 during follow-up. p values < .05 were considered statistically significant.

Conclusion générale des auteurs In conclusion, the present study provides valuable evidence for the safety and effectiveness of switching from originator to biosimilar IFX over a prolonged follow-up period of 18 months and demonstrates that switching was well tolerated and did not affect the long-term clinical outcome.

Financement de l’étude Research grants from Takeda, Ferring and Tilotts

Déclaration des conflits d’intérêts Marte L. HN.D.ivik has received unrestricted research grants from Takeda, Ferring and Tilotts and she has received speaker honorarium from MSD, MEDA, AbbVie, Bjorn Moum has been a member of advisory boards for Orion Pharma and Hospira. No potential conflict of interest was reported by the authors

Approbation éthique The study was approved as a quality assurance study by the local data protection officer.


Tableau D36 – Caractéristiques de Jaworski 2019

Auteur, année Jaworski et ses collaborateurs, 2019

Essai clinique

Nom (no) EQUIRA study, EudraCT number 2012-002009-23, NCT02638259

Phase 3


S.O.

96


Titre Switch from reference etanercept to SDZ ETN, an etanercept biosimilar, does not impact efficacy, safety, and immunogenicity of etanercept in patients with moderate-to-severe rheumatoid arthritis: 48-week results from the phase III, randomized, double-blind EQUIRA study

Objectif demonstrated similar efficacy and comparable safety and immunogenicity profile of SDZ ETN to ETN at week 24 in patients with moderate-to-severe RA who had an inadequate response to either conventional synthetic (cs) and/or biologic (b) disease-modifying anti-rheumatic drugs (DMARDs) [4]. Herein, we present the 48-week results from the study on the effects of a single switch between ETN and SDZ ETN at week 24 on efficacy, safety, and immunogenicity of etanercept.

Devis et méthode ENCAA (Extension d’un ECRA)


N=376 BS n = 186, BS/BS n=175 BR n = 190, BR/BS n=166

Critères inclusion

Patients, aged ≥ 18 years, were included if they met the following criteria: (1) RA diagnosed according to the American College of Rheumatology (ACR) 1987 or ACR/European League Against Rheumatism (EULAR) 2010 criteria [5] for ≥ 6months before baseline; (2) active disease defined as disease activity score including 28 joint count (DAS28)-C-reactive protein (CRP) ≥ 3.2; (3) CRP > 5 mg/L or erythrocyte sedimentation rate (ESR) ≥ 28 mm/h; (4) inadequate clinical response to methotrexate (MTX) at a dose of 10–25 mg/ week after optimal dose escalation according to local standards (those who had failed a csDMARD other than MTX, and any other csDMARD used in combination with MTX prior to baseline, were allowed after an appropriate wash-out period of 4 weeks); (5) MTX therapy for ≥ 3months and on a stable dose for ≥ 28 days prior to baseline; (6) stable dose of folic acid (≥5mg per week) for ≥ 28 days before baseline.

Critères exclusion

The key exclusion criteria included (1) any previous exposure to ETN; (2) treatment with any other bDMARD therapy for RA, including tumor necrosis factor (TNF) inhibitors, anti-CD20, immune-modulator drug(s), other investigational drug(s), and/or device(s) within 3months or 5 half-lives at the time of enrollment, whichever was longer; (3) previous use of > 2 bDMARDs (patients in whom bDMARDs were efficacious but withdrawn because of reasons other than efficacy failure or safety issues were not excluded); (4) functional status class IV according to the ACR 1991 revised criteria [6]; (5) systemic manifestations of RA, with the exception of Sjögren’s syndrome; (6) any active inflammatory or autoimmune diseases other than RA; and (7) tuberculosis or latent tuberculosis detected by imaging and/or by the QuantiFERON®-TB Gold test at screening.

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Intervention 24 semaines sur BR et changement sur BS pendant un autre 24 semaines self-administer 50mg SDZ ETN or ETN (Enbrel®), provided as pre-filled syringes, subcutaneously, once weekly,

Comparateur S.O.



Secondaires Efficacité semaine 48, Effets indésirables, immunogénicité

Milieu de dispensation des soins 83 study centers across 16 countries

Durée du suivi 48 semaines depuis début, 24 semaines suite au switch; February 2015 to December 2016


Puissance The sample size determination has been described previously (Assuming no difference between GP2015 and ETN, a sample size of 183 patients per treatment group was calculated (to obtain 155 evaluable patients per treatment group, with an assumed drop-out and major protocol deviation rate of 15%), which was estimated to provide 90% power for the primary endpoint analysis.)

Type The TP2 per-protocol set (PPS) consisted of all patients completing the study until week 48 without major protocol deviations

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Test [4]. The TP2 full analysis set (FAS) consisted of all patients who continued to TP2 and had at least one study assessment documented in TP2. Patients who prematurely withdrew from the study were also not included, although this was not a protocol deviation. The TP2 safety set (SAF) consisted of all patients who received at least one dose of study treatment during TP2. All efficacy analyses were performed on the TP2 PPS and repeated on the TP2 FAS. TP2 SAF was used for the safety summaries in TP2. During TP2, the “continued SDZ ETN” group was compared with the “switched to SDZ ETN” group. A repeated measures analysis of (co)variance with treatment and time as factors up to week 48 was performed for DAS28-CRP change from baseline. Change from baseline in DAS28-CRP was estimated using values up to week 48 from the same mixed-model repeated measures analysis used to analyze the primary endpoint.


The 48-week results from the EQUIRA study demonstrate that switch from ETN to the biosimilar SDZ ETN in patients with moderate-to-severe RA did not impact the efficacy, safety, or immunogenicity of a continuous etanercept therapy.

Financement de l’étude This study was funded by Hexal AG, a Sandoz company.


Janusz Jaworski reports trial payment for this research study and lecture fees from Sandoz. Marco Matucci-Cerinic reports no conflicts of interest. Hendrik Schulze-Koops reports personal fees from Sandoz/Hexal, during the conduct of the study, and grants and personal fees from Novartis, outside the submitted work. Maya Buch reports personal fees from Sandoz, during the conduct of the study. Eugeniusz J. Kucharz reports no conflict of interest. Yannick Allanore reports personal fees from Sandoz, grants and personal fees from Pfizer, and grants and personal fees from Roche, during the conduct of the study. Arthur Kavanaugh reports personal fees from Sandoz, outside the submitted work. Philip Young and Goran Babic are employees of Hexal AG.

Approbation éthique The study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization Guidelines for Good Clinical Practice and local regulations. An institutional review board or independent ethics committee at each site approved the protocol, consent form, and any other written information provided to patients or their legal representatives. All patients or their legal representatives gave written informed consent prior to study entry.


Tableau D37 – Caractéristiques de Jorgensen 2017

Auteur, année Jorgensen et ses collaborateurs, 2017

Essai clinique Nom (no) NOR-SWITCH study, NCT02148640.

Phase Phase IV


There were two amendments to the protocol during the conduct of the study. Amendment 1 dated February 12, 2015, version number 1.2: This amendment added exclusion criteria 6: "For patients with UC and CD: Functional colostomy or ileostomy. Extensive colonic resection with less than 25 cm of the colon left in situ." In addition, the protocol was amended to enable further recording of background demographic information for each patient. Amendment 2 dated July 21, version number 2.0: This amendment added details of a 26-week open-label extension with CT-P13 to the study.

Titre Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): A 52-week, randomised, double-blind, non-inferiority trial

Objectif The aim of NORSWITCH was to examine switching from originator infliximab to the less expensive biosimilar CT-P13 regarding efficacy, safety, and immunogenicity.

Devis et méthode The NOR-SWITCH study was designed as a 52-week randomised, double-blind, parallel-group, multicentre non-inferiority comparative phase 4 study. ECR


BR/BR = 241 BR/BS = 241

Critères inclusion

All of the following conditions must apply to the prospective patient at screening prior to receiving study treatment: 1. A clinical diagnosis of either rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn’s disease or chronic plaque psoriasis 2. Male or non-pregnant, non-nursing female 3. > 18 years of age at screening 4. Stable treatment of innovator infliximab (Remicade®) during the last 6 months

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5. Subject capable of understanding and signing an informed consent form 6. Provision of written informed consent

Critères exclusion

Patients will be excluded from the study if they meet any of the following criteria: 1. Major co-morbidities, such as severe malignancies, severe diabetes mellitus, severe infections, uncontrollable hypertension, severe cardiovascular disease (NYHA class 3 or 4), severe respiratory diseases and/or other diseases including inflammatory conditions for which infliximab is contra-indicated. 2. Change of major co-medication during the last 2 months prior to randomization:

• RA, SpA and PsA: Initiation of systemic corticosteroids or synthetic DMARDs or other medication which according to the investigator would interfere with the stability of the disease.

• UC and CD: Initiation of systemic corticosteroids or an immunosuppressant or other medication which according to the investigator would interfere with the stability of the disease

• Psoriasis: Initiation of methotrexate, cyclosporine or other medication which according to the investigator would interfere with the stability of the disease 3. Inadequate birth control, pregnancy, and/or breastfeeding. Adequate contraception includes oral, injected or implanted hormonal methods of contraception, placement of an intrauterine device or system, vasectomized partner or sexual abstinence. 4. Psychiatric or mental disorders, alcohol abuse or other substance abuse, language barriers or other factors which makes adherence to the study protocol impossible 5. Change in treatment with innovator infliximab (Remicade®) during the last 6 months due to disease related factors, not including dose/frequency adjustments due to drug concentration measurements 6. For patients with UC and CD: Functional colostomy or ileostomy. Extensive colonic resection with less than 25 cm of the colon left in situ.


Intervention Switch from infliximab to CT-P13



Principal The primary endpoint was disease worsening during follow-up according to worsening in disease-specific composite measures or a consensus about disease worsening between investigator and patient leading to major change in treatment. Disease worsening according to disease-specific composite measures was defined as change from baseline in Harvey-Bradshaw Index of 4 points or more and a score of 7 points or greater points for Crohn’s disease, change from baseline in Partial Mayo Score of more than 3 and a score of 5 or greater for ulcerative colitis, change from baseline in Ankylosing Spondylitis Disease Activity Score of 1·1 or more attaining a minimum score of 2·1 for spondyloarthritis, change from baseline in Disease Activity Score in 28 joints of 1·2 or more with a minimum score of 3·2 for rheumatoid arthritis and psoriatic arthritis, and change in Psoriasis Area and Severity Index of 3 or more and a score of 5 or greater for chronic plaque psoriasis

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Secondaires Secondary endpoints included time to disease worsening, study drug discontinuation, overall remission status based on the main composite measures, changes (follow-up minus baseline) in investigator and patient global assessments, and changes in erythrocyte sedimentation rate and C-reactive protein. Prespecified secondary endpoints for Crohn’s disease and ulcerative colitis were change and remission status of Harvey-Bradshaw Index and Partial Mayo Score, as well as changes in faecal calprotectin levels. In spondyloarthritis, change in Ankylosing Spondylitis Disease Activity Score and achievement of inactive disease according to this score were prespecified. Secondary endpoints for rheumatoid arthritis and psoriatic arthritis included achievement of remission according to Disease Activity Score in 28 joints, Clinical Disease Activity Index, and Simplified Disease Activity Index as well as American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) remission criteria. Other secondary endpoints were changes in Disease Activity Score in 28 joints, Clinical Disease Activity Index, and Simplified Disease Activity Index. In chronic plaque psoriasis, we prespecified complete clearance according to Psoriasis Area and Severity Index, mild to moderate disease, and remission as well as change in Psoriasis Area and Severity Index score as secondary endpoints.

Milieu de dispensation des soins Hospital setting: 25 Norwegian hospitals recruited patients to the study.



Puissance Assuming no difference between the treatment groups in the proportion of patients with disease worsening during the 52 weeks of the study, we calculated that 394 patients (197 in each group) were required in the per-protocol set to ensure with 90% confidence that the upper limit of the two-sided 95% CI would exclude a difference in favour of infliximab originator of more than 15%. An additional assumption for this estimate was an expected 30% occurrence of disease worsening. Assuming 20% exclusions from the per-protocol set, we aimed to randomise 492 patients.

Type The null hypothesis of this study was that CT-P13 would be inferior to infliximab originator with regard to the proportion of patients with disease worsening during 52 weeks of treatment by 15%. The alternative hypothesis was that CT-P13 would be non-inferior with regard to the proportion of patients with disease worsening by, at most, 15%. We regarded a non-inferiority margin of 15% as appropriate on the basis of clinical discussions within the study group, the PLANETRA study, and discussions with the Norwegian Medicines Agency.

Test We analysed the primary outcome and secondary dichotomous endpoints using logistic regression with treatment as fixed effect, adjusted for diagnosis and the treatment duration of infliximab originator at baseline providing estimates (by the delta method) of adjusted risk difference and adjusted relative risk for the treatment difference. We checked the robustness of the primary results regarding centre effect using a multilevel mixed logistic model approach with centre as random variable, and by generalised estimating equations. Continuous endpoints were examined by linear mixed models with patient-specific random intercept and treatment, time, treatment–time interaction, baseline value, diagnosis, and treatment duration of infliximab originator at baseline as fixed factors. C-reactive protein, erythrocyte sedimentation rate, and calprotectin were log-transformed before analyses because of anticipated skewed data distribution. Time to event endpoints were analysed with a Cox regression model adjusted for diagnosis and treatment duration of infliximab originator at baseline. We included subgroup analyses by diagnosis for exploratory analyses. Missing data due to dropout for the primary endpoint were imputed with the worst outcome (disease worsening) in the full analysis set.

Conclusion générale des auteurs Findings from the NOR-SWITCH trial showed that switching from infliximab originator to CT-P13 was not inferior to continued treatment with infliximab originator according to our prespecified non-inferiority margin. There was no suggestion of differences in safety or immunogenicity between the two treatment groups. Consequently, the study results support that patients can be switched from originator to biosimilar infliximab.

Financement de l’étude This trial was supported by a direct grant from the Norwegian Government, by the Ministry of Health and Care Services

Déclaration des conflits d’intérêts KKJ reports personal fees from Tillott, Intercept, and Celltrion. ICO reports grants from Norwegian Ministry of Health and Care Services during the conduct of the study. GLG reports personal fees from Orion Pharma, Pfizer, Novartis, and AbbVie. ML reports personal fees from Novartis. NB reports personal fees received from Orion Pharma (advisory board), Napp Pharmaceuticals (lecture), Pfizer (advisory board), and Takeda (lecture, booklet co-authorship). EAH reports grants from AbbVie, Pfizer, UCB, Roche, and MSD. KEAL reports grants from MSD, and personal fees from Takeda, Orion, AbbVie, Pfizer, and MSD. CM reports personal fees from Novartis Norge AS, LEO Pharma AS, ACO Hud Norge AS, Cellgene AS, Abbvie, and Galderma Nordic AB. JJ has served as a speaker, consultant or advisory board member for MSD, AbbVie,

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Celltrion, Orion Pharma, Takeda, Napp Pharm, AstroPharma, Hikma, and Pfizer. TKK reports grants from the Norwegian Ministry of Health and Care Services during the conduct of the study and personal fees from AbbVie, Biogen, BMS, Boehringer Ingelheim, Celltrion, Eli Lilly, Epirus, Janssen, Merck-Serono, MSD, Mundipharma, Novartis, Oktal, Orion Pharma, Hospira/Pfizer, Roche, Sandoz, and UCB Pharma.

Approbation éthique The study was conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. The study protocol and consent documents were approved by an independent ethics committee (Regional Committees for Medical and Health Research Ethics [REC] South East; reference number 2014/848), by appropriate institutional review boards, and by the Norwegian Medicines Agency (reference number 14/07192-11).


Tableau D38 – Caractéristiques de Kaltsonoudis 2019

Auteur, année Kaltsonoudis et ses collaborateurs, 2019

Essai clinique

Nom (no) N.D.

Phase N.D.


N.D.

Titre Maintained clinical remission in ankylosing spondylitis patients switched from reference infliximab to its biosimilar: An 18-month comparative open-label study

Objectif The aim of our study was to investigate if BI is equivalent to RI to maintain patients with AS in clinical remission compared with continuing RI in a long-term fashion.

Devis et méthode prospective observational cohort study


N= 88 BR/BS n= 45 BR/BR n=43 Ankylosing Spondylitis (AS)

Critères inclusion

Consecutive unselected patients with AS who were treated with RI in a tertiary university center. All patients were followed-up at predefined times receiving RI (5 mg/kg/8 weeks) intravenously and were naïve to previous biologic treatments. Patients who were in clinical remission were asked to switch from RI to BI using the same therapeutic dose after shared decision making.

Critères exclusion

N.D.


Intervention BR/BS receiving RI (5 mg/kg/8 weeks) intravenously, Patients who were in clinical remission were asked to switch from RI to BI using the same therapeutic dose after shared decision making.

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Comparateur BR/BR receiving RI (5 mg/kg/8 weeks) intravenously



Secondaires Effets indésirables,

Milieu de dispensation des soins tertiary university center, Greece

Durée du suivi Up to 18 months, January 2017 to December 2018


Puissance N.D.

Type N.D.

Test Statistical analysis was performed using SPSS statistics version 20.0 (IBM Corporation, Armonk, NY, USA)We used the paired samples t-test for variables with normal distribution and Wilcoxon signed ranks test for variables which were not normally distributed. A p-value < 0.05 was considered statistically significant.


This is the first study in which AS patients in clinical remission receiving RI who were switched to BI remained in clinical remission for at least 18 months. We demonstrated that BI is equivalent to RI in maintaining AS patients in clinical remission.



The authors declare no conflict of interest

Approbation éthique Written informed consent was obtained from all patients, and the study has been approved by the clinical Research Ethic Committee of the University Hospital of Ioannina, according to the principles in the Declaration of Helsinki (197/2-12-2016).


Tableau D39 – Caractéristiques de Kang 2018

Auteur, année Kang et ses collaborateurs, 2018


Phase N.D.


N.D.

Titre Long-term outcomes after switching to CT-P13 in pediatric-onset inflammatory bowel disease: A single-center prospective observational study

Objectif This study investigated the long-term efficacy, safety, pharmacokinetics, and immunogenicity of CT-P13 after switching from infliximab RP in pediatric-onset IBD patients.

Devis et méthode Prospective observational study


Seventy-four patients were recruited to the study, 60 with CD and 14 with UC.

Critères inclusion

Male or female patients with pediatric-onset IBD aged < 18 years at diagnosis, who had been receiving infliximab RP for at least 6 months.

Critères exclusion

A diagnosis of IBD-unclassified (IBD-U).

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Auteur, année Kang et ses collaborateurs, 2018


Intervention CT-P13



Principal The primary end points of this study were the proportion of patients in both groups continuously receiving infliximab (RP or CT-P13) for 1 year, and the proportion of patients achieving a persistent remission, defined as a corticosteroid-free sustained clinical remission without further dose intensification, at 1 year.

Secondaires Secondary end points included the proportion of patients who were in clinical remission, biochemical remission, and who were ADA-positive at 1 year compared with baseline, and the proportion of patients with serum trough infliximab concentrations above therapeutic levels at 1 year.

Milieu de dispensation des soins Department of Pediatrics, Samsung Medical Center



Puissance N.D.

Type Data are means ± SD for continuous variables that showed normal distribution and median [IQR] for continuous variables that did not show normal distribution. Percentage of persistent remission

Test For statistical comparison of the switch and control groups at 1 year, a Student t test or Wilcoxon rank sum test was used for continuous variables, and a chi-square test or Fisher exact test was used for categorical variables. These tests were also used for statistical comparison of data obtained at baseline and at 1 year in the CT-P13 switch group. Data were considered to be statistically significantly different if P < 0.05.

Conclusion générale des auteurs In conclusion, the current 1-year study found that switching from maintenance infliximab RP to CT-P13 did not result in any significant differences in efficacy, pharmacokinetics, or Immunogenicity in pediatric-onset IBD patients, and there were no unexpected safety issues.

Financement de l’étude Funded by CELLTRION Healthcare Co., Ltd.

Déclaration des conflits d’intérêts The authors declare no conflicts of interest

Approbation éthique This study was approved by the Institutional Review Board of the Samsung Medical Center and was conducted in accordance with the Declaration of Helsinki.


Tableau D40 – Caractéristiques de Kolar 2017

Auteur, année Kolar et ses collaborateurs, 2017


Phase N.D.


N.D.

Titre Infliximab biosimilar (RemsimaTM) in therapy of inflammatory bowel diseases patients: Experience from one tertiary inflammatory bowel diseases centre

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Objectif Our aim was to evaluate the efficiency and safety of biosimilar IFX in clinical practice in anti-TNFα-naïve IBD patients as well as of switching patients from original to biosimilar IFX, and to assess the risk of immunogenicity.

Devis et méthode Prospective


Seventy-four patients with IBD, 56 with CD and 18 with UC were switched from original to biosimilar IFX

Critères inclusion

Consecutive patients with Crohn’s disease (CD) and ulcerative colitis (UC) naïve to anti-TNFα in whom IFX therapy was indicated during a period from January 2015 to January 2016 were included. Also, consecutive patients already on a maintenance IFX treatment who came to the IBD Clinical and Research Centre between January and March 2015 and were switched from original to biosimilar IFX were observed.

Critères exclusion

N.D.


Intervention CT-P13



Principal Patients switched from original IFX were followed prospectively in regular intervals coincident with infusion applications. At each visit, disease activity was registered using the Harvey-Bradshaw index (HBI) for CD and the Simple Clinical Colitis Activity Index (SCCAI) for UC.

Secondaires IFX TLs and ATIs of both original and biosimilar IFX were measured

Milieu de dispensation des soins IBD Clinical and Research Centre



Puissance N.D.

Type Standard descriptive statistical analyses were performed, including frequency distributions for categorical data and calculation of mean and standard deviation and/or range for continuous variables.

Test The differences of continuous variables between baseline and W46 and W56 were analyzed by Wilcoxon matched-pair signed-rank test. The differences in variables between intensified and regular-dose populations were evaluated using Mann– Whitney U test. The evaluation of categorical variables difference was performed by Fisher’s exact test. A p value < 0.05 was considered statistically significant.

Conclusion générale des auteurs In conclusion, switching of IBD patients from original to biosimilar IFX seems to be effective and safe. Importantly, no increase in immunogenicity was observed. However, there is a need for further mainly randomized controlled studies with larger patient populations and longer follow-up periods.

Financement de l’étude The study was supported by the IBD-Comfort foundation

Déclaration des conflits d’intérêts The authors have no conflict of interest to disclose



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Tableau D41 – Caractéristiques de Lukas 2020

Auteur, année Lukas et ses collaborateurs, 2020


Phase S.O.


S.O.

Titre Switching from originator adalimumab to the biosimilar SB5 in patients with inflammatory bowel disease: Short-term experience from a single tertiary clinical center

Objectif Patients’ perspectives after switching from originator to biosimilar adalimumab have yet to be assessed. We evaluated the efficacy of switching from the originator adalimumab to a biosimilar compound [SB5] in patients with inflammatory bowel disease [IBD].

Devis et méthode Retrospective matched cohorts


N = 186 BR/BR: 93 BR/BS: 93

Critères inclusion

Patients who underwent a non-medical switch from originator adalimumab to the biosimilar SB5

Critères exclusion

S.O.


Intervention Switch from adalimumab to SB5

Comparateur Adalimumab


Principal The following parameters were assessed in both cohorts at Weeks 0 and 10: Harvey-Bradshaw index [HBI]9 in patients with CD and partial Mayo score [pMayo]10 in patients with UC; C-reactive protein [CRP]; faecal calprotectin [FC]; adalimumab serum trough levels [TLs]; and anti-drug [adalimumab] serum antibodies [ADA].

Secondaires S.O.

Milieu de dispensation des soins IBD Center ISCARE, Czech Republic

Durée du suivi 10 weeks; November 2018 and May 2019


Puissance N.D.

Type N.D.

Test Data were statistically evaluated using SW STATISTICA [Version 13; Tibco]. Quantitative variables were tested for normality with the Shapiro-Wilk test. Continuous variables were presented as medians and in upper and lower quartiles, and categorical variables were shown as numbers and percentages. A non-parametric Kruskal- Wallis test was carried out to analyse the agreement between data, and a chi square test was used to determine whether there was a significant difference between the frequencies of categorical variables; p-values ≤0.05 were considered significant.

Conclusion générale des auteurs In conclusion, the availability of biosimilar adalimumab could certainly result in improvements in access to a very expensive biologic treatment. In our study, we have shown the same clinical, laboratory, and pharmacokinetic outcomes of therapy with a biosimilar SB5 in comparison with the originator drug after the non-medical switch in IBD

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Auteur, année Lukas et ses collaborateurs, 2020

patients. No serious adverse event was recorded. To confirm our results, data from both randomised clinical trials and clinical practice with longer follow-up are needed.

Financement de l’étude This project was supported by IBD Comfort Foundation.

Déclaration des conflits d’intérêts The authors have no conflict of interest to declare.

Approbation éthique were analysed in accordance with the ethical principles of the Declaration of Helsinki. The project was approved by an institutional ethics committee.


Tableau D42 – Caractéristiques de Matsuno 2019

Auteur, année Matsuno et Matsubara, 2019

Essai clinique


Phase 3


N.D.

Titre A randomized double-blind parallel-group phase III study to compare the efficacy and safety of NI-071 and infliximab reference product in Japanese patients with active rheumatoid arthritis refractory to methotrexate

Objectif This study aimed to demonstrate the equivalence of NI-071, an infliximab biosimilar (BS), and the infliximab reference product (RP) for treating Japanese patients with active rheumatoid arthritis (RA) refractory to methotrexate.

Devis et méthode ENCAA (ECRA suivi d’une extension)


N = 242 BS n= 126, BS/BS n=108 BR n=116, BR/BS n= 102

Critères inclusion

Japanese active RA patients were enrolled in this study at the screening visit if they were diagnosed with RA according to the 2010 American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) [3] classification criteria, aged ≥ 20 to ≤75, weighed > 40 to < 100 kg, and showed inadequate response to previous treatment with methotrexate (MTX; receiving ≤16 mg/week with less than 2-week drug withdrawal during the 12 weeks prior to screening and a stable dose of ≥6 mg/week during 4 weeks prior to the screening). Patients were also required to have the following criteria in the screening and until treatment initiation (day 1): ≥6 tender joints and ≥6 swollen joints, ESR ≥28 mm/h, and DAS28-ESR score ≥3.2 (categories corresponding to moderate or high disease activity).

Critères exclusion

N.D.

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Intervention BR (Remicade®) pendant 30 semaines puis changement pour BS: NI-071 (Infliximab) pendant 24 semaines administered via intravenous drip infusion on day 1 (first dose) and at weeks 2 and 6 at a fixed dose of 3 mg/kg; if favorable efficacy was observed, the same dose was administered in the following duration at an 8-week interval. If the efficacy was insufficient at week 14 (based on the investigator’s discretion), a stepwise dose increase and/or shortened dose interval was allowed thereafter up to 10 mg/kg at an 8-week interval or up to 6 mg/kg at a shortened 4-week interval.

Comparateur S.O.




Milieu de dispensation des soins Multicentres in Japan

Durée du suivi 54 semaines; July 2013-March 2015


Puissance N.D.

Type modified intention-to-treat

Test The criterion for efficacy equivalence between BS and RP was defined as the 95% confidence interval (CI) of the difference in mean baseline-to-week 14 change of DAS28-ESR values to be within a range of -0.6 to +0.6 [2,6]. Other efficacy endpoints also used the same statistical method. AEs were collected by treatment group and coded by system organ class and preferred term according to MedDRA (Medical Dictionary for Regulatory Activities) version 18.0. The rate of ADA positivity among patients was calculated on day 1 (baseline), at weeks 14 and 30 prior to dosing, and at week 54, and was compared between the BS and RP groups in Period 1 using Fisher’s exact test. Trough serum concentrations of the study drugs are presented as summary statistics at weeks 14, 30, and 54 by treatment group, and were compared between the BS and RP groups in Period I by using Student’s t test.


In conclusion, this study demonstrated the equivalence of BS to RP based on efficacy and safety data. Hence, BS would be useful for the treatment of patients with RA that was inadequately controlled by MTX. Overall, BS would provide an efficacy and safety profile equivalent to RP for treating RA patients at a relatively lower cost.

Financement de l’étude All costs for manuscript development were funded by Nichi-Iko Pharmaceutical Co., Ltd.


T. Matsubara received lecture fees from Pfizer Japan Inc.; Janssen Pharmaceutical Co., Ltd.; and Astellas Pharma Inc., and research grants from IQVIA Services Japan K.K.;

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Janssen Pharmaceutical Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; Daiichi Sankyo Co., Ltd.; Astellas Pharma Inc.; Eli Lilly Japan K.K.; MSD Co., Ltd.; Nippon Kayaku Co., Ltd.; Parexel International Corp.; Pfizer Japan Inc.; and Bristol-Myers Squibb, and consulting fees from Nichi-Iko Pharmaceutical. H. Matsuno has received consulting fees from Mochida Pharmaceutical, AYUMI Pharmaceutical Corporation, Nichi-Iko Pharmaceutical and Meiji Seika Pharma, and lecture fees from Daiichi Sankyo, UCB Japan, Janssen Pharmaceutical KK, Chugai Pharmaceutical, and Ono Pharmaceutical.

Approbation éthique This study was conducted in accordance with the ethical principles of the Helsinki Declaration and in compliance with good clinical practice guidelines. The study protocol and informed consent form were reviewed and approved by the institutional review board. Written informed consent was obtained from the participating patients.


Tableau D43 – Caractéristiques de Minutolo 2017

Auteur, année Minutolo et ses collaborateurs, 2017

Essai clinique

Nom (no) N.D.

Phase N.D.


N.D.

Titre Effectiveness of switch to erythropoiesis-stimulating agent (ESA) biosimilars versus maintenance of ESA originators in the real-life setting: Matched-control study in hemodialysis patients

Objectif The aim of this study was to evaluate the efficacy on anemia control of switching from ESA originators to biosimilars in daily clinical practice.

Devis et méthode Retrospective Matched cohorts


N= 326 BR/BR n= 163 BR/BS n=163

Critères inclusion

without providing any specific indication on the selection criteria

Critères exclusion

the exclusion criteria were bleeding or blood transfusion in the 6 months prior to the switch, and treatment with doses of ESA originators [1000 IU/week] in the 3 months prior to the start observation date.


Intervention BR/BS 125 received HX575, (epoetin alfa, Binocrit®) 38 received SB309; (epoetin zeta, Retacrit®) all ESAs were administered intravenously, thrice weekly.

Comparateur BR/BR patients who continued treatment with ESA originators,

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Auteur, année Minutolo et ses collaborateurs, 2017

77 received epoetin alfa (Eprex®), 59 received epoetin beta (NeoRecormon®) 27 received darbepoetin (Aranesp®) all ESAs were administered intravenously, thrice weekly except once weekly for darbepoetin.


Principal Effectiveness

Secondaires N.D.

Milieu de dispensation des soins 12 non-profit Italian dialysis centers, Italie

Durée du suivi January 2011–October 2014


Puissance N.D.

Type N.D.

Test N.D.


This study provides first-time evidence in daily clinical practice that switching from ESA originators to biosimilars is associated with poorer anemia control, despite a significant dosing difference of approximately 40%. This finding is also relevant from an economic point of view and it is important to correctly plan resource allocation.

Financement de l’étude None.


Roberto Minutolo has received payment for lectures from Amgen and Roche, and a travel grant from Janssen. Luca De Nicola has received payment for lectures from Janssen and Roche. Domenico Russo has received payment for lectures from Amgen, Janssen, and Kerix. Piergiorgio Bolasco, Paolo Chiodini, Stefano Sposini, Maurizio Borzumati, Cataldo Abaterusso, Alessandra A. Mele, Domenico Santoro, Valeria Canale, Alberto Santoboni, Oliviero Filiberti, Fulvio Fiorini, Carlo Mura, Patrizio Imperiali, Silvio Borrelli, and Luigi Russo have no conflicts of interest to declare

Approbation éthique All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/ or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.


Tableau D44 – Caractéristiques de Nikiphorou 2015

Auteur, année Nikiphorou et ses collaborateurs, 2015

Essai clinique

Nom (no) N.D.

Phase N.D.


N.D.

Titre Clinical effectiveness of CT-P13 (Infliximab biosimilar) used as a switch from Remicade (infliximab) in patients with established rheumatic disease. Report of clinical experience based on prospective observational data

Objectif To gain clinical experience on the effectiveness and safety of switching from infliximab-Remicade® (INX) to infliximab-biosimilar-CT-P13 (INB) in patients with established rheumatic disease.

Devis et méthode ENCAA (prospective observational cohort study)


N=39 BR/BS n=39

Critères inclusion

established rheumatic diseases already receiving INX (±methotrexate) for a period of 3 months to 13 years were identified and switched to INB

Critères exclusion

N.D.

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Intervention BR/BS infliximab-Remicade® (INX) to infliximab-biosimilar-CT-P13 (INB) with established rheumatic diseases already receiving INX (±methotrexate) for a period of 3 months to 13 years were identified and switched to INB. The majority of patients were diagnosed with RA (38%), the remainder were AS (36%), psoriatic arthritis (PsA) (18%) juvenile idiopathic arthritis (JIA) (5%) and chronic reactive arthritis (3%) patients.

Comparateur N.D.


Principal Clinical effectiveness of biological drugs before and after switch as measured by comparable parameters across all disease groups: disease activity, PROs and drug survival

Secondaires safety and recording of reasons for drug discontinuation where indicated.

Milieu de dispensation des soins Jyväskylä Central Hospital, Finland

Durée du suivi median (range) of 11 (7.5 to 13) months after the first administration of INB.


Puissance N.D.

Type N.D.

Test Descriptive statistics were used to compare average disease activity levels and PROs before and after switch from INX to INB using variables that are applicable across all diagnosis groups. Time-dependent area under the curve (AUC) was computed to each variable for time elapsed before biologic treatment, during INX and INB treatments. Repeated measures were analyzed using generalized estimating equations (GEE) models with an unstructured correlation structure.


Based on the results from our clinical experience, no major safety issues were encountered and INB seems to be well tolerated and with disease outcomes that are comparable between INX and INB. This is based on a short follow-up of up to 13 months

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and although small and uncontrolled, this report provides important new data on switching from INX to INB. Results from RCTs will be necessary to formally assess safety and clinical efficacy across various patient and disease parameters and with higher patient numbers and longer follow-up.

Financement de l’étude Hospira Nordic provided a grant to Prof Sokka-Isler & the hospital to conduct an investigator led register-based study. N.D.


Hospira did not have any role in the design, conduct, or reporting of the results; this was the responsibility of the investigator and her group. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.



Tableau D45 – Caractéristiques de Papp 2017

Auteur, année Papp et ses collaborateurs, 2017

Essai clinique


Phase 3


N.D.

Titre Clinical similarity of biosimilar ABP 501 to adalimumab in the treatment of patients with moderate to severe plaque psoriasis: A randomized, double-blind, multicenter, phase III study

Objectif We sought to compare the efficacy and safety of ABP 501 with adalimumab

Devis et méthode ECRA; This randomized, double-blind, multicenter, active-controlled phase III trial


N= 350 BR n= 175, 16 weeks n=156; BR/BS n= 77; BR/BR n= 79 BS/BS n= 175

Critères inclusion

Patients 18 to 75 years of age who had stable moderate to severe plaque psoriasis for at least 6 months and were candidates for phototherapy or systemic therapy and who had inadequately responded to or were unable to tolerate or receive at least 1 conventional systemic therapy were eligible for enrollment. Patients were required to have disease involvement of 10% or more of the body surface area, a Psoriasis Area and Severity Index (PASI) score of 12 or more (scores range from 0-72, with higher scores indicating more severe disease), and a static Physician Global Assessment of at least moderate severity (6-point scale, assessment ranges from clear to very severe) Patients must have had no evidence of active tuberculosis according to local guidelines; women of childbearing potential were required to use contraception.

Critères exclusion

Patients with nonplaque psoriasis, drug-induced psoriasis, or any other skin condition that might interfere with evaluation of efficacy were excluded. Patients who previously used adalimumab or a biosimilar of adalimumab, or any 2 or more biologics for psoriasis were also excluded. Other therapies not permitted during the study included ultraviolet B light and most topical therapies, except upper mid strength to least potent topical steroids and bland emollients, within 14 days of first study treatment dose; ultraviolet A light (with or without psoralen), excimer laser, and nonbiologic systemic therapies within 28 days of first study treatment dose; etanercept within 1 month before screening; and any other anti-TNF agent or ustekinumab within 3 months before screening.

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Intervention BR/BS switched from originator adalimumab to biosimilar ABP 501

Comparateur BR/BR Adalimumab BS/BS biosimilar ABP 501


Principal Efficacity at week 16

Secondaires Efficacity, Safety

Milieu de dispensation des soins 3 Research Sites; Australia, Canada and Hungary

Durée du suivi 52 weeks; October 2013 to March 2015


Puissance A sample size of 340 patients was calculated to provide greater than 90% power to demonstrate clinical equivalence at a .025 significance level.

Type N.D.

Test Efficacy data were analyzed using the full analysis set, which included all patients initially randomized in the study with missing values imputed using the last observation carried forward method. The safety analysis included all randomized patients who received at least 1 dose of study drug, and the immunogenicity analysis included patients in the safety analysis who had at least 1 evaluable antibody test result. Clinical equivalence for the primary end point was evaluated by comparing the 2-sided 95% confidence interval (CI) of the difference in PASI percent improvement from baseline to week 16 between treatment groups with the equivalence margin of 615. The 2-sided 95% CI of the group difference was estimated using an analysis of covariance with baseline PASI score and stratification factors of geographic region and prior biologic use as covariates. Descriptive statistics were provided for secondary efficacy assessments. Safety and immunogenicity data were summarized descriptively through week 16 and post-week 16 (after rerandomization) through week 20, which included data for the patients transitioned from adalimumab to ABP 501 (adalimumab/ ABP 501).


In summary, this randomized, double-blind study demonstrated clinical similarity of ABP 501 to adalimumab in percent PASI improvement at week 16. Similar efficacy to the reference product was also shown in a variety of secondary assessments. The safety profiles of the treatment groups were comparable through 16 weeks, and there was no impact on safety and immunogenicity after a single transition from adalimumab to ABP 501.

Financement de l’étude Amgen Inc funded this study and participated in the design and conduct of the study; collection, management, analysis, and interpretation of data; and preparation, review, and approval of the manuscript. All authors were involved in the decision to submit the manuscript for publication and had the right to accept or reject comments or suggestions. A medical writer employed by MedVal Scientific Information Services LLC and funded by Amgen Inc participated in the writing of this manuscript and is acknowledged.


Dr Papp has served as a consultant, speaker, scientific officer, steering committee member, investigator, or advisory board member for3M, Abbott, Akesis, Akros, Alza, Amgen, Astellas, Baxter, BMS, Boehringer Ingelheim, CanFite, Celgene, Cipher,

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Dermira, Eli Lilly, Forward Pharma, Funxional Therapeutics, Galderma, GSK, Isotechnika, Janssen, Johnson & Johnson, Kirin, Kyowa, Lypanosys, MedImmune, Merck-Serono, Mitsubishi Pharma, MSD, Novartis, Pfizer, Roche, Takeda, UCB, Valeant, and Vertex. Dr Bachelez has served as a consultant, speaker, steering committee member, investigator, or advisory board member for AbbVie, Amgen, Baxalta, Boehringer-Ingelheim, Celgene, Janssen, LEO Pharma, Lilly, MSD, Novartis, Pfizer, and Takeda, and received grant support from Pfizer. Dr Costanzo has been an investigator/consultant and speaker for AbbVie, Amgen, Celgene, Janssen, Lilly, Novartis, and Pfizer. Dr Foley has served as a consultant, investigator, speaker, and/or advisor for, and/or received travel grants from Galderma, LEOPharma/Peplin, Ascent,Clinuvel, Janssen-Cilag, Eli Lilly, Australian Ultraviolet Services, Roche, CSL, 3M/iNova/Valeant, GSK/ Stiefel, Abbott/AbbVie, Biogen Idec, Merck Serono, Schering- Plough/MSD, Wyeth/Pfizer, Amgen, Novartis, Celgene, Aspen, Boehringer Ingelheim, and BMS. Dr Gooderham has been an investigator, consultant, and/or speaker for AbbVie, Amgen, Boehringer Ingelheim, Celgene, Coherus, Dermira, Galderma, Janssen, LEO Pharma, Lilly, Medimmune, Merck Serono, Novartis, Regeneron, Roche, Sanofi Genzyme, Takeda, and Pfizer. Dr Kaur is an Amgen employee and stockholder. Dr Narbutt is an investigator for Amgen. Dr Philipp has been investigator, consultant, and/or speaker for AbbVie, Amgen, Almirall, Biogen, Boehringer-Ingelheim, BMS, Celgene, Janssen, LEO Pharma, Lilly, MSD, Novartis, Pfizer, and UCB. Dr Spelman has served on advisory boards for Galderma, Novartis, and AbbVie; undertakes sponsored clinical research for AbbVie, Amgen, Anacor, Ascend Biopharmaceuticals, Astellas, Australian Wool Innovation Limited, Blaze Bioscience, Celgene, Dermira, Eli Lilly, Galderma, Genentech, GlaxoSmith Kline, Kythera, LEO Pharma, Merck, Novartis, Phosphagenics, Regeneron, and Trius; and has received sponsored travel from Abbott, Novartis, and Janssen-Cilag. Dr Weglowska has been an investigator for Amgen, Pfizer, Novartis, Galderma, Eli Lilly, Dermira, Roche, Janssen-Cilag, Coherus, Genentech, LEO Pharma, Merck, Mylan, and Regeneron. Dr Zhang is an Amgen employee and stockholder. Dr Strober has served on a speakers bureau for AbbVie, receiving honoraria; is a consultant and advisory board member for AbbVie, Amgen, Astra Zeneca, Celgene, Dermira, Forward Pharma, Janssen, LEO Pharma, Eli Lilly, Cutanea-Maruho, Medac, Novartis, Pfizer, Sun, Stiefel/GlaxoSmithKline, UCB, and Boehringer Ingelheim, receiving honoraria for all; is an investigator for AbbVie, Amgen, GlaxoSmithKline, Novartis, Lilly, Janssen, Merck, XenoPort, Xoma, Celgene (payments to the University of Connecticut); is scientific director for Corrona Psoriasis Registry, receiving a consulting fee; received grant support to the University of Connecticut for a fellowship program from AbbVie and Janssen

Approbation éthique This study was conducted in accordance with the current International Conference on Harmonization Good Clinical Practice Guidelines and the Declaration of Helsinki. The study protocol was approved by the institutional review board or independent ethics committee at each participating site and adhered to all local regulatory requirements including data protection requirements. Written informed consent was obtained from each patient before study enrollment.


Tableau D46 – Caractéristiques de Park 2017 (CT-P10)

Auteur, année Park et ses collaborateurs, 2017

Essai clinique


Phase 1


N.D.

Titre Efficacy and safety of switching from innovator rituximab to biosimilar CT-P10 compared with continued treatment with CT-P10: Results of a 56-week open-label study in patients with rheumatoid arthritis

Objectif This open-label extension (OLE) study compared the efficacy and safety of CTP10 in patients with RA who received CT-P10 from the outset (i.e., from the start of the RCT and also in the OLE; ‘maintenance group’) with those who received RTX during the RCT and switched to CT-P10 during the OLE (‘switch group’).

Devis et méthode ECRA open label

114



N = 154 BS n= 103, BS/BS n=58 BR n=51, BR/BS n= 29

Critères inclusion

patients with active RA aged 18–75 years who had been diagnosed according to the revised 1987 American College of Rheumatology classification for at least 6 months and had shown an inadequate response or intolerance to anti-TNF therapy. Additional inclusion criteria for this OLE study included disease improvement during the last course of treatment in the RCT [according to Disease Activity Score using 28 joint counts (DAS28) combined with erythrocyte sedimentation rate (DAS28-ESR) or serum C-reactive protein (DAS28-CRP)], and completion of all scheduled visits in that study with no major protocol violations.

Critères exclusion

Exclusion criteria included any medical problem that meant continued participation could be detrimental to the patient’s health according to the investigator’s opinion.


Intervention BR rituximab (RTX) pendant 48 semaines puis changement pour BS: CT-P10 pendant 56 semaines

Comparateur S.O.




Milieu de dispensation des soins Korea (1 site)

Durée du suivi 56 weeks; February 2012 to February 2014


Puissance N.D.

Type N.D.

Test Descriptive statistics were used to analyze efficacy and safety data in the maintenance and switch groups. Efficacy parameters were also compared between groups using cumulative logistic regression and t tests. The efficacy analysis population consisted of all patients who received at least one dose of CT-P10 and provided data for at least one efficacy endpoint in the OLE study. The safety population included all patients who received at least one dose of study treatment in the OLE.


This study demonstrated that switching from RTX to CTP10 had no notable impact on the efficacy or safety of treatment in this population of patients with RA. Comparable improvements in RA disease activity and response rates were observed in patients who continued CT-P10 treatment in this OLE study and also in those who had switched from RTX to CT-P10. In addition, CT-P10 was shown to be efficacious and well-tolerated in patients with active RA treated repeatedly with this biosimilar for up to 2 years.

115


Financement de l’étude The study was sponsored by CELLTRION, Inc. (Incheon, Republic of Korea). The funding body contributed to the design of the study, the collection, analysis, and interpretation of data, and the review of drafts and final version of the manuscript.


WP received consulting fees during the conduct of the study and grants outside the submitted work from CELLTRION. PH and SR received grants form CELLTRION for conducting the clinical trial. MJL received grants from CELLTRION during the conduct of the study. SJL is an employee of, and holds stock options in, CELLTRION. SYL and SHK are employees of CELLTRION. DHY is a scientific consultant and on the speaker’s bureau of CELLTRION and has received research grants not related to this clinical study. C-HS, SCS, FFCM, SJ, FGM-R, PW, EYL, PS, VK, LM, MS, and J-YC declare no conflicts of interest.

Approbation éthique This study was performed according to the principles of the Declaration of Helsinki and International Conference on Harmonization Good Clinical Practice guidelines. Study protocols and consent forms were approved by the relevant independent ethics committees. The following ethical bodies approved the study in the centers involved—Brazil: Comiteˆ de E ´ tica em Pesquisa da Associac ¸aõ de Assisteˆncia a` Criança Deficiente; Comiteˆ de E ´ tica em Pesquisa do Hospital de Clıńicas da Universidade Federal do Parana´; Republic of Korea: IRB of IN-HA University Hospital; SNUMC/ SNUH IRB; IRB of Daegu Catholic University Medical Center; Mexico: Comite´ de E ´ tica ICLE SC; Comite´s de E´ tica e Investigacioń en Salud Centro de Especialidades Me´dicas del Sureste SA de CV; Comite´ de E ´ tica e Investigacioń para Estudios en Humanos del ‘‘Hospital Me´dica Sur’’ S.A.B de C.V.; Comite´ Bioetico para la Investigacioń Clıńica S.C; Poland: The Bioethics Committee at the Regional Medical Council of Wielkopolska Medical Chamber; Russia: Council on Ethics, Annex to the Order of the Ministry of Healthcare of the Russian Federation; Spain: Comite´ E ´ tico de Investigacioń Clıńica de Andalucıá; Ukraine: Commission on Ethics Questions of State Institution National Scientific Center.


Tableau D47 – Caractéristiques de Park 2017 (CT-P13)


Essai clinique


Phase OLE


N.D.

Titre Efficacy and safety of switching from reference infliximab to CT-P13 compared with maintenance of CT-P13 in ankylosing spondylitis: 102-week data from the PLANETAS extension study

Objectif To investigate the efficacy and safety of switching from infliximab reference product (RP) to its biosimilar or maintaining biosimilar treatment in patients with ankylosing spondylitis (AS).

Devis et méthode ENCAA (Extension d’un ECRA)


N= 250 BS n= 125, BS/BS n= 88 BR n= 125, BR/BS n= 86

Critères inclusion

patients aged 18–75 years with active AS for ≥3 months according to the 1984 modified New York classification criteria. Patients who had completed 54 weeks of the main PLANETAS study were offered the opportunity of entering the extension study for another 1 year. Additional eligibility criteria applied for the extension study were no major protocol violation in the main study and no new therapy for AS in the extension.

Critères exclusion

Those who did not sign a new informed consent form for the extension were excluded.

116



Intervention Patients in the extension study received an additional six infusions of CT-P13 given every 8 weeks from week 62 to week 102. CT-P13 was administered via 2 h intravenous infusion at a dose of 5 mg/kg. At the discretion of the investigator, antihistamines could be provided 30–60 min before CT-P13 infusion.

Comparateur N.D.


Principal Efficacy assessments

Secondaires immunogenicity, safety

Milieu de dispensation des soins 40 centres in 8 countries.

Durée du suivi 40 weeks; March 2012 to May 2013


Puissance N.D.

Type intent-to-treat (ITT)

Test Statistical analyses were conducted using SAS software V.9.1.3 (SAS Institute, Cary, North Carolina, USA). Continuous data were summarised using descriptive statistics. Categorical data were summarised using counts and percentages. The populations were predefined in the study protocol and statistical analysis plan for participants in the extension study. The intent-to-treat (ITT) population consisted of all enrolled patients. The efficacy population consisted of all patients who received at least one full dose of study treatment and had data for at least one efficacy assessment in the extension study. All efficacy analyses were performed using a ‘missing equals excluded’ (MEX) approach. A logistic regression model was used to analyse the proportion of patients achieving clinical response (ASAS20/ASAS40/ASAS PR), with treatment group as a fixed effect and the stratification factors (baseline BASDAI score and region) as covariates. Treatment effect differences between maintenance and switch groups were estimated by calculating ORs and their 95% CI. Descriptive statistics were used to analyse other efficacy end points. The safety population (used to analyse all safety and immunogenicity events) consisted of all patients who received at least one dose of study treatment in the extension study. Data from the main study period were analysed in participants of the extension study only, and not in all patients from the main study. Methods for sensitivity analyses of ASAS responses are included in online supplementary appendix A.


CT-P13 was well tolerated with comparable efficacy and safety as the historical infliximab RP treatment in patients with AS over 102 weeks. Furthermore, switching from the infliximab RP to CT-P13 after 1 year of infliximab RP treatment showed continued comparable efficacy, immunogenicity and safety, to maintenance of CT-P13 treatment during the 2nd year of the treatment.

Financement de l’étude This study was funded by CELLTRION Inc (Incheon, Republic of Korea).


DHY and WP: Consultation for Celltrion. MB has received research grants from Celltrion, personal fees from lectures for Roche, Abbvie, MSD, Pfizer, Egis, UCB outside the submitted work; JB has received honoraria for talks, advisory boards, paid consultancies or grants for studies from Abbvie (Abbott), Amgen, Boehringer Ingelheim, Bristol-Myers-Squibb, Celgene, Celltrion, Centocor, Chugai, EBEWE Pharma, Janssen, Medac, MSD

117


(Schering-Plough), Mundipharma, Novartis, Pfizer (Wyeth), Roche, Sanofi-Aventis and UCB. HUK, SJL, YJB and SYK are full-time employees of Celltrion. Otherwise, none declared.

Approbation éthique Patient consent: Obtained. The protocol was reviewed and approved by each site’s institutional review board or independent ethics committee.


Tableau D48 – Caractéristiques de Pescitelli 2019

Auteur, année Pescitelli et ses collaborateurs, 2019

Essai clinique

Nom (no) N.D.

Phase N.D.


N.D.

Titre Clinical experience with the etanercept biosimilar SB4 in psoriatic patients

Objectif To study safety and efficacy of SB4 in psoriatic patients previously treated with etanercept and in the etanercept naive ones.

Devis et méthode ENCAA (prospective observational cohort study)


N= 44 BR/BS n= 32 BS n=12 with moderate to severe plaque psoriasis.

Critères inclusion

Patients affected by moderate to severe psoriasis (Pso) and/or psoriatic arthritis (PsA), attending the Psoriasis Center of Florence University Dermatological Unit, and treated with SB4 were included in the study.

Critères exclusion

N.D.


Intervention BR/BS Switch from Etanercept (Enbrel®, Amgen/Pfizer) to SB4 (Benepali©, Samsung Bioepis/Biogen) (50 mg weekly)

Comparateur N.D.



Secondaires Effets indésirables,

Milieu de dispensation des soins Psoriasis Center of Florence University Dermatological Unit, Italy



Puissance N.D.

Type N.D.

Test Analysis of variance (repeated measures ANOVA)

118

Auteur, année Pescitelli et ses collaborateurs, 2019


Switching from originator to SB4 in psoriatic patients seems to not influence efficacy, especially for cutaneous manifestations over a median observational period of 6 months. Regarding the efficacy on articular symptoms we found a mild decrease in efficacy. The incidence of sporadic mild adverse events before and after switching did not differ and consistent with the safety profile of the ETN molecule. All cutaneous events were mild to moderate in severity and easily manageable with emollients and antihistamines. No severe infections were reported.

Financement de l’étude None


The authors declare that they have no conflict of interest.

Approbation éthique This study was approved by our local ethics committee.


Tableau D49 – Caractéristiques de Petitdidier 2019

Auteur, année Petitdidier et ses collaborateurs, 2019


Phase S.O.


S.O.

Titre Patients’ perspectives after switching from infliximab to biosimilar CT-P13 in patients with inflammatory bowel disease: A 12-month prospective cohort study

Objectif The aim of this study was to assess patients’ perspectives concerning infliximab biosimilars after switching from infliximab toCT-P13 during a 1-year period on a prospective basis. In addition, the effectiveness, safety and trough concentrations of CT-P13 were also assessed on a prospective basis.



BR/BS n = 113

Critères inclusion

Inclusion criteria included the following: diagnosis of IBD according to ECCO criteria classified as CD, UC or IBD unclassified [5,15]; on-going maintenance therapy with infliximab(REMICADE®) at a stable dose for at least six months; stable steroid-free clinical remission for at least six months according to the Harvey-Bradshaw index (HBI) for patients with CD and partial Mayo Clinic score for patients with UC; switch from infliximab to CT-P13 (INFLECTRA®); age > 18 years; and absence of pregnancy.

Critères exclusion

N.D.

119



Intervention Switch from Infliximab to CT-P13

Comparateur S.O.


Principal The primary outcomes were measured as a change in the BMQ score between the screening visit and the fourth CT-P13 infusion.

Secondaires Secondary outcomes included changes in the IBD-DI score, the FACIT-F score, the 11-item questionnaire about knowledge, beliefs and concerns about biosimilars, and the rates of steroid-free clinical remission and adverse events. A steroid-free clinical remission was defined as an HBI ≤4 for CD patients and a partial Mayo Clinic score<3 with a combined stool frequency and rectal bleeding sub score of ≤1 without steroids [17,18,20]. Relapse was defined as an HBI>4 for patients with CD and partial Mayo score > 3 for patients with UC. Steroid-free means the absence of any dose of any oral steroid(prednisone, prednisolone and/or budesonide) and includes the rectal use of betamethasone. Safety was assessed by the physician in charge. Severe adverse events were defined as the occurrence of treatment interruption, hospitalization, disability, persistent damage, colectomy or death.

Milieu de dispensation des soins 1 center in France



Puissance N.D.

Type N.D.

Test All of the included patients were evaluated from the inclusion visit through week 52. The data are expressed as a number (%) for qualitative data and mean ± the standard deviation (SD) or median [interquartile range] for quantitative data. Hazard ratios (HRs) were provided with 95% confidence intervals (CIs). The proportions of patients with steroid-free clinical remission were compared at every time point using the chi-squared test. Quantitative data were compared at every time point using Wilcoxon’s matched-pair signed-rank test. All analyses were computed relative to the whole population included at week 0. Event-free (without loss of clinical remission, infusion reaction and/or need for a new course of steroid) survival was calculated using the Kaplan–Meier method. The survival distributions were compared using the log-rank test. To identify the independent factors, a Cox proportional hazard model was adjusted with an ascending stepwise procedure. Variables with p < 0.10 in univariate analysis were considered to be potential

120


adjustment variables for the multivariate analysis. The continuous variables were dichotomised according to the median value. All analyses were two-tailed, and p-values less than 0.05were considered significant. All statistical evaluations were performed using SPSS (SPSS Inc., v17, Chicago, IL, USA).

Conclusion générale des auteurs In conclusion, our results confirm the effectiveness and safety of CT-P13 after switching from infliximab to CT-P13 for maintenance therapy in a real-world setting. Switching from infliximab to CT-P13 had no impact on fatigue and IBD-related disability and did not alter the doctor-patient relationship or patient beliefs on medication and possibly adherence.


Déclaration des conflits d’intérêts Charlotte Gagnière received travel accommodations from Takeda. Iradj Sobhani received travel accommodations from Biocodex, Pfizer, IPSEN, Novartis. Aurelien Amiot received consulting fees from Abbvie, Hospira, Takeda, Gilead and Biocodex as well as lecture fees and travel accommodations from Abbvie, Grifols, Janssen, Biocodex, Ferring, Takeda and MSD. This author has also received advisory board fees from Gilead, Takeda and Abbvie.No conflicts of interest are claimed by the remaining authors.

Approbation éthique The protocol was approved by the Comité Consultatif sur le Traitement de l’Information en Matière de Recherche dans le Domaine de la Santé (CCTIRS; no. 16-249) and the Commission Nationale de l’Informatique et des Libertés (CNIL; no. 1955334).


Tableau D50 – Caractéristiques de Plevris 2019

Auteur, année Plevris et ses collaborateurs, 2019


Phase N.D.


N.D.

Titre Implementation of CT-P13 via a managed switch programme in Crohn's disease: 12-month real-world outcomes

Objectif The aim of this work was to prospectively evaluate clinical outcomes in a cohort of patients with Crohn’s disease switching from Remicade® to CT-P13

Devis et méthode A prospective service evaluation


A total of 155 patients with CD on maintenance treatment with Remicade® entered the switch pathway

Critères inclusion

All CD patients on maintenance treatment with Remicade® were identified from our infusion suite records.

Critères exclusion

N.D.


Intervention CT-P13


121

Auteur, année Plevris et ses collaborateurs, 2019


Principal Harvey-Bradshaw Index (HBI), CRP, IFX trough and antibody levels as well as faecal calprotectin (FC) were obtained

Secondaires All adverse events during follow-up were documented.

Milieu de dispensation des soins Tertiary IBD centre in Edinburgh, Scotland.



Puissance N.D.

Type Descriptive statistics are presented as medians with interquartile range (IQR) for continuous variables and number with percentages for categorical variables

Test The correlation between IFX levels and HBI/CRP/FC was determined by Spearman’s correlation test. For comparison of non-parametric continuous variables, the Mann-Whitney U test was used. Comparison of parameters at the three different time points [baseline (final Remicade® infusion), 6 months and 12 months] was done using Freidman analysis and if significant pairwise comparison at each time point was carried out using the Wilcoxon signed rank test. We performed an intention-to-treat analysis with the last observation carried forward for patients who discontinued CT-P13. p < 0.05 was considered significant.

Conclusion générale des auteurs In conclusion, we have shown no significant impact on clinical and safety outcomes in patients switching from Remicade® to CT-P13 for the treatment of CD.


Déclaration des conflits d’intérêts NP has received consultancy fees from Takeda and speaker fees and travel support from AbbVie, Takeda and Norgine. EFW has received travel support from AbbVie. SD has received travel support from AbbVie and Dr. Falk. CLN has received consultancy fees from Vifor. AGS has received travel support from AbbVie. IDA has received consultancy fees from Vifor and travel support from Shire. CWL has received research support from AbbVie and Shire, consultancy fees from AbbVie, Pfizer, Dr. Falk, Hospira, MSD, Pharmacosmos, Takeda and Vifor, and speaker fees and travel support from AbbVie, Pfizer, Dr. Falk, Ferring, Hospira, MSD, Shire, Takeda and Warner-Chilcott. GRJ, PWJ, ML, CSC, LMM, RJP, and GTH have no personal interests to declare.

Approbation éthique Following review, this work was considered a service evaluation/ audit as all data were collected as part of routine clinical care. Therefore, no formal ethical approval or written consent was necessary as per departmental policy and Health Research Authority guidance. Caldicott guardian approval (NHS Lothian) was granted for anonymised data collection, analysis and submission for publication without the need for formal written consent. This piece of work conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a prior approval by the institution’s review board.


Tableau D51 – Caractéristiques de Ratnakumaran 2018

Auteur, année Ratnakumaran et ses collaborateurs, 2018


Phase N.D.


N.D.

Titre Efficacy and tolerability of initiating, or switching to, infliximab biosimilar CT-P13 in inflammatory bowel disease (IBD): A large single-centre experience

Objectif We aim to assess the efficacy and safety of switching from originator infliximab to CT-P13 for new and existing patients.

Devis et méthode Observational study, prospective


Switch / non-switch : 210 patients were receiving maintenance infliximab originator therapy for IBD. Of these, 191 (91.0%) patients consented to switch to CT-P13, and 19 (9.0%) continued on the originator.

Critères inclusion

Patients who were receiving infliximab originator therapy (Remicade®) for CD or UC in our center.

Critères exclusion

N.D.

122

Auteur, année Ratnakumaran et ses collaborateurs, 2018


Intervention CT-P13



Principal Treatment remission and response rates, secondary loss of response rates, and adverse events were compared

Secondaires N.D.

Milieu de dispensation des soins IBD outpatient clinic in Leeds Teaching Hospitals Trust, Leeds, United Kingdom



Puissance N.D.

Type All continuous data were analysed using a mean with a standard deviation, and all ordinal data were averaged using a median with an inter-quartile range.

Test All categorical data were measured as proportions, and compared between groups using the Pearson v2 statistic, or Fisher’s exact test where cell counts were small. p values<.05 were considered statistically significant.

Conclusion générale des auteurs Overall, CT-P13 is a cheaper, safe and effective alternative to infliximab originator. These data highlight that there is no difference in remission, response, loss of response or adverse events when initiating or switching to CT-P13 compared with initiating or continuing infliximab originator for IBD.


Déclaration des conflits d’intérêts A.C.F. has received speakers’ fees from MSD. P.J.H. has served on advisory boards and received speakers’ fees from MSD.

Approbation éthique The study was conducted as a prospective clinical audit and relevant clinical audit authorisation was obtained. Due to the nature of audit, research ethics committee approval and informed consent were not required.


Tableau D52 – Caractéristiques de Razanskaite 2017

Auteur, année Razanskaite et ses collaborateurs, 2017


Phase N.D.


N.D.

Titre Biosimilar infliximab in inflammatory bowel disease: Outcomes of a managed switching programme

Objectif Biosimilar infliximab CT-P13 offers the potential for large drug acquisition cost savings. However, there are limited published data regarding its efficacy, safety, and immunogenicity in inflammatory bowel disease [IBD], particularly in switching IBD patients from originator to biosimilar infliximab. We present the outcomes of a service evaluation of switching IBD patients established on originator infliximab to biosimilar, using a managed switching programme funded via a gain share agreement in a UK teaching hospital.

Devis et méthode Prospective, observational


All 143 patients with IBD (118 Crohn’s disease [CD], 23 ulcerative colitis [UC], 2 IBD unclassified [IBDU])

Critères inclusion

All patients with IBD

Critères exclusion

N.D.

123

Auteur, année Razanskaite et ses collaborateurs, 2017


Intervention CT-P13



Principal The evaluation outcomes included drug persistence, changes in drug acquisition costs, patient-reported side effects, adverse events, a patient-reported outcome measure (the IBD Control Patient-Reported Outcome Measures [PROM]12), infliximab trough and antibody levels, and routinely collected blood tests including C-reactive protein [CRP], platelet count, haemoglobin, and albumin.

Secondaires N.D.

Milieu de dispensation des soins University Hospital Southampton



Puissance N.D.

Type Descriptive statistics were used to characterise patients’ demographics, drug withdrawal rates, and adverse events.

Test The statistical significance of difference between the IBD Control PROM score at baseline and at third dose of CT-P13 was assessed using Wilcoxon signed rank test; data were non-normally distributed. The differences in mean biochemical values and drug levels were measured using a paired Student’s t test. Drug persistence was evaluated using survival curves for originator and biosimilar infliximab and compared using log-rank test. All two-sided p-values below 0.05 were considered significant.

Conclusion générale des auteurs In conclusion, we have presented the development, implementation, and early outcomes of a successful managed switching programme, using a gain share agreement to ensure that all stakeholders were appropriately incentivised to allow significant service development while delivering significant savings to the health economy.

Financement de l’étude The measurement of drug trough levels and antidrug antibodies was performed by Royal Devon and Exeter NHS Foundation Trust and was funded by an unrestricted grant to University Hospital Southampton NHS Foundation Trust by Hospira.

Déclaration des conflits d’intérêts FC has received speaker/consultancy fees or research support from Hospira, NAPP pharmaceuticals, MSD, Abbvie, Janssen, Takeda pharmaceuticals, and Biogen. The other authors have no conflicts of interest in the authorship or publication of this contribution.



Tableau D53 – Caractéristiques de Rosenstock 2015

Auteur, année Rosenstock et ses collaborateurs, 2015

Essai clinique

Nom (no) ELEMENT-2; NCT01421459

Phase 3.


N.D.

Titre Similar efficacy and safety of LY2963016 insulin glargine and insulin glargine (Lantus®) in patients with type 2 diabetes who were insulin-naïve or previously treated with insulin glargine: A randomized, double-blind controlled trial (the ELEMENT 2 study)

124


Objectif To compare the efficacy and safety of LY2963016 insulin glargine (LY IGlar) and the reference product (Lantus®) insulin glargine (IGlar) in combination with oral anti hyperglycaemic medications in patients with type 2 diabetes (T2D).

Devis et méthode ECRA, phase III, randomized, multinational, multicentre, two-arm, active-controlled, double-blind, parallel study. Devient ENCAA, avant après


N= 759 BR/BS n= 155; Naïfs/BS n= 220 BR/BR n= 144; Naïfs/BR n= 235

Critères inclusion

Eligible study participants had T2D based on World Health Organisation diagnostic criteria 24, were aged ≥18 years, had been receiving ≥2 oral anti hyperglycaemic medications at stable doses for 12 weeks before screening (with or without IGlar), had HbA1c levels ≥7.0 and ≤11.0% if insulin‐naïve or ≤11.0% if previously on IGlar, and had a body mass index ≤45 kg/m2

Critères exclusion

Exclusion criteria included treatment with pramlintide (Symlin®) or any other insulin except IGlar within the previous 30 days, treatment with a biosimilar insulin glargine within the previous 90 days, history of receiving basal‐bolus therapy or, in the investigator's opinion, requirement for mealtime insulin to achieve target control, total daily insulin dose ≥1.5 U/kg, and more than one episode of severe hypoglycaemia within the past 6 months.


Intervention BR/BS Naifs/BS LY IGlar

Comparateur BR/BR Naïfs/BR IGlar (Lantus®)


Principal Change from Baseline up to 24 Weeks in Hemoglobin A1c (HbA1c)

Secondaires Change from Baseline in Insulin Antibody Levels, plus 12 others

Milieu de dispensation des soins Element-2: 62 locations in 12 countries

Durée du suivi Element-2: 28 weeks, September 2011 to September 2012


Puissance The non-inferiority design is in accordance with regulatory requirements [26–28]. Based on the primary objective, to show non-inferiority of LY IGlar to IGlar at the 0.4% non-inferiority margin (NIM), and 0.3% NIM if the 0.4% NIM was met, 284 (568 total) completers per arm were needed at 24weeks. This calculation assumed no treatment difference inHbA1cbetween LY IGlar and IGlar, a common standard deviation of 1.1% for change from baseline in HbA1c, 0.05 two-sided significance level and 90% power for a

125


0.3% NIM, and > 99% power for a 0.4% NIM. Assuming a 15% dropout rate at 24weeks, the required number of randomized patients was 334 per arm (668 total).


Test Analyses were conducted using sas version 9.1.3 (SAS Drug Development, Cary, NC, USA) and were based on all patients who were randomized and took ≥1 dose of study drug, defined as the full analysis set, a slightly modified intent-to-treat population. If the measurement for a visit was missing, the previous non-missing measurement was analysed using the last-observation-carried-forward (LOCF) methodology. All tests of treatment effects were conducted at a two-sided 𝛼 level of 0.05 and confidence intervals (CIs) were calculated as two-sided 95% CIs. All tests of interactions between treatment groups and other factors were conducted at a two-sided 𝛼 level of 0.05. No adjustments for multiplicity were performed. The primary efficacy measure was the change in HbA1c from baseline to the 24-week endpoint, defined as the value at 24weeks or LOCF. The primary analysis model was an analysis of covariance (ancova) for the change from baseline to endpoint with pooled country, sulphonylurea use (yes or no), time of basal insulin injection (daytime or evening/bedtime), and treatment as fixed effects and baseline HbA1c as a covariate. The primary treatment comparison was to compare LY IGlar with IGlar at the NIM of 0.4%. If the upper limit of the 95% CI on the change in HbA1c from baseline to the 24-week endpoint for LY IGlar versus IGlar was < 0.4%, then LY IGlar was declared non-inferior to IGlar. If the 0.4% NIM was met, then the upper limit of the 95% CI was compared with the 0.3% NIM. This gate-keeping procedure controlled the family-wise type 1 error rate at a one-sided 0.025 level. A key secondary treatment comparison was to compare IGlar with LY IGlar at the NIMof −0.4%; therefore, if LY IGlar was declared non-inferior to IGlar in the primary treatment comparison as described above, and IGlar was also declared non-inferior to LY IGlar in the secondary treatment comparison, then LY IGlar was considered to have equivalent efficacy to IGlar. The analysis of the continuous secondary efficacy outcomes used the ancova model which was used for the primary efficacy outcome. The proportion of patients achieving HbA1c target values (HbA1c < 7.0 and ≤6.5%) during the study was analysed using Fisher’s exact test. Hypoglycaemia rate, expressed as events per patient per year, was analysed using a negative binomial model with terms for treatment and other stratification variables. A subgroup analysis of the HbA1c levels examined the consistency of the treatment effect for the subgroup defined by entry basal insulin treatment. The change in HbA1c from baseline to 24-week endpoint (LOCF) was analysed using ancova with treatment, country, sulphonylurea use (yes or no), time of basal insulin injection (daytime or evening/bedtime) as fixed effects and baseline HbA1c as a covariate, and the subgroup [i.e. entry basal insulin treatment (IGlar, none)], and subgroup-by-treatment interaction. Similar subgroup analyses were performed for other efficacy outcomes.


Upon switching basal insulin from IGlar U100 to IGlar biosimilar or IGlar U300, patients can expect similar HbA1c and body weight changes. Patients in whom hypoglycemia is already a problem before switching should be switched to IGlar U300. IGlar biosimilar is a suitable option for patients with a low risk of hypoglycemia. clinical trial showing effective glucose-lowering and similar safety and efficacy profiles for LY IGlar and IGlar in the total study population, as well as in both insulin-naïve and previously insulin-treated subgroups of patients with T2D, add to the totality of the evidence showing the similarity of LY IGlar to IGlar. LY IGlar provides a well-tolerated and effective once-daily basal insulin option for treatment of patients with T2D in combination with oral agents.

Financement de l’étude This study was funded by Eli Lilly and Company and Boehringer-Ingelheim.


J. R. has served on scientific advisory panels, served as a consultant and received research support from insulin manufacturers Eli Lilly and Company, Sanofi and Novo Nordisk. P. H. has served on scientific advisory panels for Johnson & Johnson, Merck, Novo Nordisk and Roche Pharmaceuticals. A. B. has received research support from Abbvie, AstraZeneca Pharmaceuticals, Boehringer Ingelheim Pharmaceuticals Inc., Duke Clinical Research Institute, Eli Lilly and Company, Halozyme Therapeutics, Jaeb,Mylan, Novo Nordisk Inc., Orexigen Therapeutics Inc., Sanofi-Aventis, University of Oxford. L. L. I., W. J. H, J. S. Z., R. K. P. and M. J. P. are employees of and hold stock in Eli Lilly and Company.

Approbation éthique The study was conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki [23]. All patients provided written informed consent


126

Tableau D54 – Caractéristiques de Scherlinger 2018

Auteur, année Scherlinger et ses collaborateurs, 2018

Essai clinique

Nom (no) N.D.

Phase N.D.


N.D.

Titre Switching from originator infliximab to biosimilar CT-P13 in real-life: The weight of patient acceptance

Objectif To explore acceptance and retention rate of biosimilar CT-P13 after switching from originator infliximab (OI) in patients with various rheumatic diseases.

Devis et méthode prospective cohort study


N= 200 BR/BS n= 89 (75 (84%) spondyloarthritis (SpA), including 63 (84%) with axial involvement and 12 (16%) with PsA) BR n= 82 (64 (78%) with SpA and18 (22%) with RA) BS n= 29 (24(83%) with SpA and 5 (17%) with RA)

Critères inclusion

they presented a RA according to the 2010 ACR/EULAR criteria, or an ankylosing spondylitis (AS) or a psoriatic arthritis (PsA) according to the 2009 ASAS criteria they were treated with infliximab, in monotherapy or in association with conventional synthetic DMARDs (csDMARDs), under stable infliximab treatment regimen for at least 6 months. the disease was controlled according to the physician opinion.

Critères exclusion

N.D.


Intervention BR/BS patients were switched to CT-P13 at the same treatment regimen (dose and time interval) than previous originator infliximab (OI). Associated treatments including csDMARDs were not modified at inclusion.

Comparateur •a cohort of infliximab-naïve patients starting anti-TNF-alpha treatment with CT-P13. •a retrospective cohort of patients treated with OI during the year 2013.


Principal retention rate of CT-P13 in the switched cohort.

Secondaires •the comparisons of the retention rate of CT-P13 in the switched cohort versus the historic OI cohort and the CT-P13 initiation cohort. •the acceptance of the switch. •the reasons for switch failure. •the predictive factors of switch failure.

Milieu de dispensation des soins University Hospital of Bordeaux, France

Durée du suivi This cohort was prospectively followed from November 2015 to October 2016.


Puissance N.D.

Type N.D.

127

Auteur, année Scherlinger et ses collaborateurs, 2018

Test Quantitative variables, expressed as mean with standard deviation or median with range, were compared using a bilateral Student comparison test. Qualitative variables, expressed as proportions, were compared using a X2-test, or Fisher’s exact test if needed. Kaplan–Meier survival curves of retention rate were compared using a log-rank test. Multivariate analysis was conducted using a logistic regression test including all variables associated with the studied outcome with a P-value < 0.15 in the univariate analysis. AP-value less than 0.05 was considered as statistically significant.


Real-life experiences on the switch from an originator drug to its biosimilar for economic reasons are important for rheumatologists while the patent of many biologic DMARDs is expiring, leading toa rapid increase of the offering of biosimilars. In this respect, our work adds reassuring data to those of DANBIO and NOR-SWITCH studies concerning the efficacy and safety of the switch from OI toCT-P13; however, the main originality in our study is to emphasize the key role of patient acceptance of switching for a non-medical reason and highlights the value of the information given to patients.

Financement de l’étude Not applicable.


Interest TS received honoraria as consultant from: Amgen, AbbVie, BMS, Janssen, MSD, Novartis, Pfizer, Roche Chugaï, UCB.CR received honoraria as consultant from: Abbvie, BMS, MSD, Pfizer, Roche, UCB. BB received honoraria as consultant from Pfizer& Lilly; he received support from MSD for attending a scientific meeting. TS & CR received a research grant from Pfizer (unrelated to this work). The other authors declare that they have no competing interest.

Approbation éthique They had to give orally their consent, after clear information on the bioequivalence between OI and CT-P13. Patients were asked if they agreed to participate to the studyand were informed that it will be possible to switch back to OI if they (or the physician) considered that the efficacy or the tolerance of the new treatment was not equivalent than with OI.


Tableau D55 – Caractéristiques de Schmitz 2017

Auteur, année Schmitz et ses collaborateurs, 2017 (APT)


Phase N.D.


N.D.

Titre Switching from infliximab innovator to biosimilar in patients with inflammatory bowel disease: A 12-month multicentre observational prospective cohort study

Objectif To study prospectively the switch from infliximab innovator to biosimilar in an IBD cohort with 12 months follow-up to evaluate safety and effectiveness.

Devis et méthode ECNAA - prospective


Our cohort consisted of 133 IBD patients, of which approximately two-third had CD and one-third had UC.

Critères inclusion

All adult IBD patients treated with infliximab in were included

Critères exclusion

N.D.


Intervention Biosimilar Inflectra®


128

Auteur, année Schmitz et ses collaborateurs, 2017 (APT)


Principal Infliximab trough levels, antibodies-to infliximab (ATI), CRP and ESR were measured and disease activity scores were calculated.

Secondaires N.D.

Milieu de dispensation des soins Maxima Medical Center (Veldhoven, the Netherlands) and Elkerliek hospital (Helmond, the Netherlands)



Puissance N.D.

Type N.D.

Test First, data were analysed with the Shapiro-Wilk test to determine if it was normally distributed. This was not the case, so non-parametric statistical analysis was used. Comparison of infliximab, CRP and ESR levels between the four time points was done using Friedman analysis. If Friedman analysis returned a statistically significant difference, the Wilcoxon signed rank test was subsequently used to analyse differences between all time points in pairs. For comparison of the disease activity scores, the score at T0 was compared to the average score after switching to biosimilar therapy. This was done using the Wilcoxon Mann-Whitney test. P < .05 were considered statistically significant.

Conclusion générale des auteurs In conclusion, we found no differences in drug levels and disease activity between infliximab biosimilar and innovator in our IBD cohort, indicating that the biosimilar is safe and effective. A relatively high proportion of patients discontinued biosimilar therapy within the first year, but this is probably due to the nonblinded setup of our study and the fact that a real-life cohort was monitored rather than a well-defined and pre-selected population, which induces the nocebo effect.


Déclaration des conflits d’intérêts None



Tableau D56 – Caractéristiques de Schmitz 2018

Auteur, année Schmitz et ses collaborateurs, 2018

Essai clinique

Nom (no) N.D.

Phase N.D.


N.D.

Titre Therapeutic drug monitoring (TDM) as a tool in the switch from infliximab innovator to biosimilar in rheumatic patients: Results of a 12-month observational prospective cohort study

Objectif The objective of this study is to apply therapeutic drug monitoring (TDM) as an objective tool to monitor the switch from infliximab innovator (INX) to infliximab biosimilar (INB) in our diverse rheumatic cohort in daily clinical practice.

Devis et méthode ENCAA (prospective cohort study)


N= 27 BR/BS n= 27 Rheumatoid arthritis (RA) 14 (52%) Psoriatic arthritis (PsA) 5 (19%) Ankylosing spondylitis (AS) 4 (15%) Spondylo arthritis (SpA) 1 (3.7%) Psoriasis (PsO) 1 (3.7%) Polyarthritis with ulcerative colitis 1 (3.7%) Periferal arthritis with ulcerative colitis 1 (3.7%)

Critères inclusion

All patients from the Department of Rheumatology of Máxima Medical Center on Remicade® treatment and ≥18 years were included.

Critères exclusion

N.D.

129

Auteur, année Schmitz et ses collaborateurs, 2018


Intervention BR/BS infliximab innovator (Remicade®) to infliximab biosimilar (Inflectra®) IFX dose (mg) = 300 (300–400) Interval (weeks) = 7 (6–8)

Comparateur N.D.


Principal Therapeutic drug monitoring

Secondaires Efficacity, safety

Milieu de dispensation des soins Department of Rheumatology of Máxima Medical Center, the Netherlands

Durée du suivi 12 months after switch.


Puissance N.D.

Type N.D.

Test Infliximab, CRP, ESR levels, and disease activity scores were compared between the different time points using nonparametric Friedman analysis, the Wilcoxon signed rank test, and the Wilcoxon Mann-Whitney test.


In conclusion, we found that TDM is a helpful tool to monitor patients switching from innovator infliximab to biosimilars, and we believe thus that TDM should always guide dosing of IFX therapy. No differences in drug levels and disease activity scores were observed between INX and INB in our small but diverse cohort of patients with rheumatic diseases. Switching to biosimilar and performing TDM can make IFX therapy much more cost-effective.



None.

Approbation éthique Compliance with ethical standards


Tableau D57 – Caractéristiques de Shim 2019

Auteur, année Shim et ses collaborateurs, 2019

Essai clinique


Phase 3


S.O.

Titre Efficacy and safety of switching from rituximab to biosimilar CT-P10 in rheumatoid arthritis: 72-week data from a randomized Phase 3 trial

Objectif To evaluate the efficacy and safety of CT-P10, a rituximab biosimilar after a single switch, during a multinational, randomized, double-blind Phase 3 trial involving patients with RA.

Devis et méthode ECRA, double-blind, parallel-group, active-controlled Phase 3 study


N= 372

130


BR1 n= 151, BR1/BR1 n= 64 ou BR1/BS n= 62 BR2 n= 151, BR2/BS n= 47 BS n= 161, BS/BS n= 122

Critères inclusion

eligible patients were aged 18-75 years, had active RA, received MTX (7.5-25 mg/week orally or parenterally) for at least the past 12 weeks (with the final 4 weeks before screening at a stable dose), and had experienced an inadequate response or intolerance to TNF antagonists. Eligibility criteria for the extension period included completion of the main period up to week 48 and that they met predefined safety criteria irrespective of clinical response (absolute neutrophil count ≥ 1.5 X 109 cells/L, platelet count ≥ 75 X 109 cells/L, aspartate aminotransferase or alanine aminotransferase ≤2.5 times upper limit of normal, and levels of immunoglobulin G ≥ 500 mg/dL at the last blood sample analysis; and the patient had not developed any condition that, in the investigator’s opinion, precluded the patient receiving further courses of treatment).

Critères exclusion

N.D.


Intervention BS : CT-P10 One treatment course comprising two intravenous infusions of study drug (1000mg CT-P10) separated by a 2-week interval, co-administered with MTX (7,5_25 mg/week orally or parenterally) and folic acid (55 mg/week orally)

Comparateur BR1: US-RTX (Rituximab®, Genentech) BR2 : EU-RTX (Rituximab®, Roche) One treatment course comprising two intravenous infusions of study drug (1000mg US-RTX or EU-RTX) separated by a 2-week interval, co-administered with MTX (7,5_25 mg/week orally or parenterally) and folic acid (55 mg/week orally)


Principal Pharmacocinétique

Secondaires Efficacité, Effets indésirables, immunogénicité

131


Milieu de dispensation des soins conducted in 76 centers in Europe, Asia Pacific, and Latin America

Durée du suivi 72 semaines (48 semaines pour phase 1 et 24 semaines pour extension)


Puissance N.D.

Type N.D.

Test Continuous data were described using descriptive statistics (n, mean, S.D.), median, minimum and maximum) unless otherwise specified. Categorical data were reported using patient counts and percentages. Baseline was defined as last non-missing value on or before the first infusion of the first treatment course in the main period. The patient populations analysed are described in the Supplementary Methods, available at Rheumatology online. All analyses were conducted using Statistical Analysis System (SAS) software v9.1.3 (SAS Institute, Cary, NC, USA).


In conclusion, this Phase 3 extension study demonstrated that switching from US-RTX or EU-RTX after two treatment courses had no adverse effect on the efficacy, PD, immunogenicity and safety of a third treatment course with CT-P10, vs patients who remained on CT-P10 or US-RTX throughout the three treatment courses. CT-P10 appears efficacious and well tolerated up to week 72 in patients with RA.

Financement de l’étude This work was supported by CELLTRION, Inc. (Incheon, Republic of Korea). The study sponsor was involved in the following: study design; the collection, analysis and interpretation of data; writing of the report; and the decision to submit the paper for publication.


L.B.-M. received fees from CELLTRION for conducting the trial. P.M. received fees from CELLTRION for conducting the trial and has received fees from CELLTRION for performing trials outside the submitted work. W.P. received consulting fees from CELLTRION during the conduct of the study. C.-H.S. received consulting fees (<$10 000) and grants outside the submitted work from CELLTRION. S.J.L., S.Y.L. and Y.J.B. are employees of CELLTRION. D.H.Y. is a scientific consultant and on the speaker’s bureau of CELLTRION, on the speaker’s bureau of Celltrion Healthcare, and has received research grants from CELLTRION not related to this clinical study. The other authors have declared no conflicts of interest.



Tableau D58 – Caractéristiques de Sieczkowska 2016

Auteur, année Sieczkowska et ses collaborateurs, 2016


Phase N.D.


N.D.

Titre Switching between infliximab originator and biosimilar in paediatric patients with inflammatory bowel disease. Preliminary observations

Objectif The growing incidence of inflammatory bowel disease (IBD) in children necessitates the use of biological treatments. Recently, an infliximab biosimilar was authorized in the European Union, which may result in switching patients. We present our preliminary experiences with such switches.

Devis et méthode Prospective study


A total of 32 paediatric patients with CD and 7 paediatric patients with UC

Critères inclusion

Pediatric patients who had been treated with infliximab preparations

Critères exclusion

N.D.

132

Auteur, année Sieczkowska et ses collaborateurs, 2016


Intervention CT-P13

Comparateur infliximab originator


Principal Disease severity, laboratory parameters and adverse events were recorded.

Secondaires N.D.

Milieu de dispensation des soins Polish academic centres

Durée du suivi Different for each patient, > 16 weeks


Puissance N.D.

Type All data were expressed as means or medians, standard deviations and ranges

Test Statistical analysis was conducted with the Wilcoxon signed rank test.

Conclusion générale des auteurs This analysis showed that treatment with infliximab originator and biosimilar produces similar results. Infliximab biosimilar seems to be as effective and safe as its originator.

Financement de l’étude No funding was received for this study.

Déclaration des conflits d’intérêts J. Kierkus reports having received speaker fees from Egis, MSD and AbbVie.



Tableau D59 – Caractéristiques de Smits 2019

Auteur, année Smits et ses collaborateurs, 2019


Phase N.D.


N.D.

Titre Drug survival and immunogenicity after switching from Remicade to biosimilar CT-P13 in inflammatory bowel disease patients: Two-year follow-up of a prospective observational cohort study

Objectif We aimed to investigate the long-term drug survival, immunogenicity, and pharmacokinetics 2 years after switching to CT-P13 in IBD patients.

Devis et méthode Prospective, observational cohort study


83 patients who switched from Remicade® to CT-P13. Fifty-seven patients had CD, 24 had UC, and 2 were IBD-U.

Critères inclusion

All Remicade®-treated IBD patients switched to CT-P13 without changes to dosing and interval.

Critères exclusion

N.D.

133



Intervention CT-P13

Comparateur Infliximab (Remicade®)


Principal Main endpoints for this report were trough levels (TLs) and the development of ADAs

Secondaires Other clinical endpoints were the change in disease activity scores, discontinuation, drug survival,

Milieu de dispensation des soins Radboud University Medical Center, a tertiary IBD referral center in the Netherlands.



Puissance N.D.

Type Results are reported as median (inter-quartile range [IQR]).

Test We analyzed the change over the 4 time points (weeks 0, 16, 52, and 104) with the Friedman ANOVA test for skewed continuous variables. A P value < 0.05 was considered statistically significant. In case the Friedman ANOVA test shows a statistically significant difference, the Wilcoxon matched-pair rank test is used to test differences between time points in pairs. We performed an intention to treat analysis, and data from patients who discontinued CT-P13 were recorded according to the “latest observation carried forward” method.

Conclusion générale des auteurs In conclusion, 66% of IBD patients continued CT-P13 beyond 2 years after switching from Remicade® in a prospective observational cohort. Main reasons for discontinuation were loss of response, adverse events, and stable disease remission. Two new cases with ADAs were observed in year 1, but no immunogenicity was detected beyond week 52. These results are reassuring and suggest that switching to CT-P13 does not impact long-term clinical outcomes.

Financement de l’étude No relevant funding reported.

Déclaration des conflits d’intérêts DJ received consulting fees from Synthon Pharma, Abbvie, and MSD and travel fees from Falk Pharma, Takeda, Abbvie, MSD, Ferring, Vifor Pharma, and Cablon Medical. FH has served on advisory boards of MSD, Takeda, Celltrion, and Dr. Falk and served as a consultant for Celgene. JD has served on advisory boards of Janssen, AbbVie, BMS, and Gilead and served as a consultant for Gilead. His department receives research funding from Gilead, Abbvie, Ipsen, and Novartis.

Approbation éthique This study was approved by the local ethics committee (2015-#1922).


134




Phase N.D.


N.D.

Titre Long-term clinical outcomes after switching from Remicade® to biosimilar CT-P13 in inflammatory bowel disease

Objectif To investigate long-term efficacy, safety, pharmacokinetic profile, and immunogenicity.

Devis et méthode Prospective observational cohort study


Eighty-three patients were included (57 Crohn’s disease, 24 ulcerative colitis, and 2 IBD unclassified)

Critères inclusion

All Remicade®-treated IBD patients switched to CT-P13 in May–June 2015, regardless of disease activity

Critères exclusion

N.D.


Intervention CT-P13



Principal Primary endpoint was change in disease activity scores

Secondaires Secondary endpoints included C-reactive protein (CRP), fecal calprotectin (FCP), infliximab trough levels (TL), antidrug antibodies to infliximab (ADA), and drug survival.

Milieu de dispensation des soins IBD referral center in Nijmegen, the Netherlands.



Puissance N.D.

Type Results are reported as median (range minimum–maximum).

Test We analyzed differences between week 0 versus week 52 with the Wilcoxon matched pair signed rank test in case of skewed continuous variables. Differences between subgroups were analyzed with Chi-square for dichotomous variables and Mann–Whitney U for skewed continuous variables. A p value \0.05 was considered statistically significant. We performed an intention to treat analysis, and the ‘‘latest observation carried forward’’ method was used to record data from patients who discontinued CT-P13.

Conclusion générale des auteurs In conclusion, our one-year data on switching from Remicade® to biosimilar CT-P13 in a real-life cohort of IBD patients demonstrated no significant impact on clinical outcomes that included disease activity, safety, drug survival, and pharmacokinetics. These outcomes support feasibility for switching to CT-P13.

135



Déclaration des conflits d’intérêts Conflict of interest DJ received consulting fees from Synthon Pharma, Abbvie, and MSD, and travel fees from Falk Pharma, Takeda, Abbvie, MSD, Ferring, Vifor Pharma, and Cablon Medical. FH has served on advisory boards of MSD, Takeda, Celltrion, and Dr. Falk and served as a consultant for Celgene. JD has served on advisory boards of Janssen, AbbVie, BMS, Gilead, and served as a consultant for Gilead. His department receives research funding from Gilead, Abbvie, Ipsen, and Novartis.

Approbation éthique Compliance with ethical standards





Phase N.D.


N.D.

Titre Clinical outcomes following a switch from Remicade® to the biosimilar CT-P13 in inflammatory bowel disease patients: A prospective observational cohort study

Objectif We aimed to prospectively investigate efficacy, safety, pharmacokinetic profile, and immunogenicity following a switch from Remicade® to CT-P13 in IBD patients.

Devis et méthode Single-centre prospective observational open-label study


83 IBD patients who switched to CT-P13. The cohort consisted of 57 CD patients, 24 UC patients, and two patients with IBD-unclassified [IBD-U]

Critères inclusion

All IBD patients treated with Remicade® in our center switched to CT-P13.

Critères exclusion

N.D.


Intervention CT-P13

Comparateur Infiximab (Remicade®)


Principal The primary endpoint was change of disease activity at week 16 [±2 weeks] after switching to CT-P13 relative to week 0

Secondaires Other disease activity endpoints included serum C-reactive protein [CRP] and faecal calprotectin [FCP], Quality of life

Milieu de dispensation des soins Inflammatory Bowel Disease Centre of the Radboud university medical centre, Nijmegen, a tertiary IBD referral centre in the Netherlands.


Puissance N.D.

136



Type Results are reported as median [range minimum–maximum].

Test Differences between skewed continuous variables at week 0 versus week 16 were analysed with the Wilcoxon matched pair signedrank test. McNemar’s test was used for any change in nominal data. A p value < 0.05 was considered statistically significant. Data from patients who discontinued CT-P13 were recorded according to the ‘latest observation carried forward’ method.

Conclusion générale des auteurs In conclusion, we have demonstrated that switching from Remicade® to CT-P13 in a real-life cohort of IBD patients did not have significant impact on short-term clinical outcomes. These results suggest that switching from Remicade® to CT-P13 for the treatment of IBD is feasible.

Financement de l’étude No relevant funding reported

Déclaration des conflits d’intérêts DJ received consulting fees from Synthon Pharma, Abbvie, and MSD, and travel fees from Falk Pharma, Takeda, Abbvie, MSD, Ferring, Vifor Pharma, and Cablon Medical.

Approbation éthique The requirement for informed consent was waived as concluded by the local Medical Ethics Review Committee [2015-#1922].


Tableau D62 – Caractéristiques de Smolen 2018

Auteur, année Smolen et ses collaborateurs, 2018

Essai clinique

Nom (no) NCT01936181; EudraCT number: 2012-005733-37.

Phase 3


The protocol was amended during this period to accommodate the transition design.

Titre Safety, immunogenicity and efficacy after switching from reference infliximab to biosimilar SB2 compared with continuing reference infliximab and SB2 in patients with rheumatoid arthritis: Results of a randomised, double-blind, phase III transition study

Objectif Efficacy, safety and immunogenicity results from the phase III study of SB2, a biosimilar of reference infliximab (INF), were previously reported through 54 weeks. This transition period compared results in patients with rheumatoid arthritis (RA) who switched from INF to SB2 with those in patients who maintained treatment with INF or SB2.

Devis et méthode ECRA double-blind parallel group study


N= 805 BS n= 291, BS/BS n= 201 BR n= 293, BR/BR n= 101 ou BR/BS n= 94

Critères inclusion

Those who completed the week 54 visit of the randomised, double-blind period and were willing to participate were eligible for the transition period. The study originally enrolled patients. Patients who were 18–75 years old with RA classified by the 1987 American College of Rheumatology (ACR) classification criteria for RA were enrolled; patients had to have had RA for at least 6 months with least six tender joints and six swollen joints; an erythrocyte sedimentation rate (ESR) of ≥28 mm/h or a C reactive protein of ≥1.0 mg/dL was required. Patients had to take MTX for at least 6 months and had to be under a stable dose for at least 4 weeks before randomisation.

Critères exclusion

Patients who experienced any significant medical condition(s) during the randomised, double-blind period, such as the occurrence of a serious AE (SAE) or intolerance of SB2 or INF, and who were determined to be unfit for further treatment were excluded.

137



Intervention SB2 Treatment with SB2 or INF was initiated at an intravenous dose of 3 mg/kg at week 0. The dose could have been increased stepwise by 1.5 mg/kg, up to a maximum of 7.5 mg/kg, starting at week 30 and every 8 weeks thereafter if the patient’s RA symptoms were not well controlled by the existing dose. At the time of switching to SB2 from INF (or continuing INF or SB2 in the other arms), the dosing schedule continued from the last dose applied before switching (ie, week 54). An oral or parenteral stable dose of methotrexate (10–25 mg/week) was taken with folic acid (5–10 mg/week) throughout the study

Comparateur Remicade®, Treatment with INF was initiated at an intravenous dose of 3 mg/kg at week 0. The dose could have been increased stepwise by 1.5 mg/kg, up to a maximum of 7.5 mg/kg, starting at week 30 and every 8 weeks thereafter if the patient’s RA symptoms were not well controlled by the existing dose. At the time of switching to SB2 from INF (or continuing INF or SB2 in the other arms), the dosing schedule continued from the last dose applied before switching (ie, week 54). An oral or parenteral stable dose of methotrexate (10–25 mg/week) was taken with folic acid (5–10 mg/week) throughout the study




Milieu de dispensation des soins The study was conducted in 73 centres in 11 countries from Europe and Asia

Durée du suivi 24 semaines


Puissance Sample size and power calculations based on the primary endpoint of the study (ACR20 response at week 30) were previously described. The primary objective was to demonstrate equivalence of ACR20 at week 30. To determine equivalence between SB2 and INF the 95% CI of the ACR20 rate difference had to be within the prespecified margin of −15% and +15%. The equivalence margin was determined using data from

138


several INF studies4,18,19 and regulatory guidelines.20, 21 Sample size was calculated assuming this equivalence margin of ±15%, an11 pays73) effect size of 57% and a 20% dropout rate. With a significance level of 5% and a power of 80%, a sample size of at least 292 randomised patients per treatment group was required in order to reach the required subject size for the PPS.


Test All results obtained during the transition period were analysed using descriptive statistics. Efficacy results were based on the extended full analysis set (Ex-FAS), which follows the intent-to-treat principle and comprises available data (ie, no imputation) in all patients who were re-randomised at week 54 and who received at least one dose of SB2 or INF during the transition period. To evaluate efficacy changes over the entire duration of the study in the three treatment groups, a retrospective analysis of efficacy was performed in the Ex-FAS population from week 54 back to week 0. AEs and immunogenicity were analysed in the extended safety set (Ex-SAF), which comprised all patients who received at least one dose of SB2 or INF during the transition period. Analyses were performed using SAS V.9.2.


SB2, an INF biosimilar, maintained comparable efficacy, safety and immunogenicity up to 78 weeks, even after switching from the originator INF. Our results suggest that the clinical profile of SB2, when administered long term or when switched from INF, is comparable with INF.

Financement de l’étude This study was funded by Samsung Bioepis Co., Ltd.


JSS reports receiving grant/research support from AbbVie, Janssen, MSD, Pfizer, Roche and UCB; consultant for AbbVie, Amgen, AstraZeneca, Astro-Pharma, Celgene, GSK, Janssen, Lilly, Medimmune, MSD, Novartis-Sandoz, Novo Nordisk, Pfizer, Roche, Samsung Bioepis, Sanofi and UCB. J-YC reports receiving grant/research support and consultant fees from Samsung Bioepis. AB reports receiving grant/research support from AbbVie and Samsung Bioepis. NP, JN, IS, ED, RY, MM, WP, HC, KJ-R and AZ report receiving grant/research support from Samsung Bioepis. YL and YHR are employees of Samsung Bioepis and own stocks in Samsung Biologics.

Approbation éthique Ethics approval was received from each national regulatory agency and central or local ethical committee.


Tableau D63 – Caractéristiques de Strik 2018

Auteur, année Strik et ses collaborateurs, 2018

Essai clinique Nom (no) SECURE (2014-004904-31)

Phase Phase 4


N.D.

Titre Serum concentrations after switching from originator infliximab to the biosimilar CT-P13 in patients with quiescent inflammatory bowel disease (SECURE): An open-label, multicentre, phase 4 non-inferiority trial

Objectif We aimed to show that infliximab serum concentrations with biosimilar CT-P13 are non-inferior to those with originator infliximab after switching from originator infliximab in patients with inflammatory bowel disease.

Devis et méthode SECURE was an open-label, multicentre, prospective, phase 4 trial


120 consecutive patients with inflammatory bowel disease: 59 with ulcerative colitis and 61 with Crohn’s disease

Critères inclusion

Eligible patients were aged 18 years or older; had a confirmed diagnosis of ulcerative colitis or Crohn’s disease; were in clinical remission, which was defined as a score on the Simple Clinical Colitis Activity Index (SCCAI) of less than 2·5 for patients with ulcerative colitis or a score on the Harvey-Bradshaw Index (HBI) of 4 or less for patients with Crohn’s disease; and on continuous treatment with originator infliximab for more than 30 weeks at dosing intervals of 7–9 weeks. Patients who were receiving combination therapy were eligible, but doses of concomitant immunomodulators had to be stable for at least 4 months.

Critères exclusion

Pregnant or nursing people; those with psychiatric disorders or major comorbidities, such as severe diabetes, tuberculosis, severe infections, uncontrollable hypertension, severe cardiovascular disease (New York Heart Association class 3 or 4), or severe respiratory diseases; and those taking another biological drug or a non-registered new chemical entity were excluded.

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Intervention CT-P13



Principal Our primary outcome was change in serum concentrations of infliximab between baseline and 16 weeks for ulcerative colitis and Crohn’s disease separately.

Secondaires Secondary endpoints were CT-P13 infliximab serum concentrations 8 weeks after switching; anti-drug antibodies to infliximab at 8 weeks and 16 weeks; C-reactive protein concentrations at baseline, 8 weeks, and 16 weeks; faecal calprotectin concentrations at baseline and 16 weeks; clinical disease activity (as measured with the SCCAI in ulcerative colitis and the HBI in Crohn’s disease) at baseline, 8 weeks, and 16 weeks; and quality of life measured with the generic EQ-5D questionnaire at week 16 compared with baseline. Safety endpoints included incidence and type of adverse events, which were classified as treatment related or not treatment related and graded as mild, moderate, or severe. Adverse events were assessed up to 30 days after discontinuation.

Milieu de dispensation des soins 13 academic and non-academic sites



Puissance The sample size was calculated on the basis of a coefficient of variation of 50%, an expected ratio of means of 1, a one-sided α of 0·05, a correlation of at least 0·7 between infliximab serum concentrations at baseline and 16 weeks, and a non-inferiority margin of 15%. We calculated that, to achieve 90% power, 42 patients were needed per disease type in the per-protocol analysis. Assuming that 20% of patients would be excluded from the per-protocol population, a minimum of 53 patients needed to be recruited per disease type to allow for subgroup analysis with equal allocation.

Type The study was a non-inferiority trial, with the ratio of infliximab serum concentrations at week 16 to those at baseline as the outcome. Non-inferiority was established, at a significance level of 5%, if the lower limit of the two-sided 90% CI for the geometric mean of this ratio was above 100% minus δ (the non-inferiority margin). We used a non-inferiority margin of 15%, which is in line with the registration trials of CT-P13.2,3

Test Least-squares point estimates for the geometric mean of the ratio and a two-sided 90% CI were computed per disease group. ANOVA of the change from baseline scores for the secondary endpoints at weeks 8 and 16 was done, and the overall within-group effect was tested. We deemed p values less than 0·05 to be significant. If the ANOVA was significant, we did post-hoc tests to establish where these differences occurred. The assumptions of the ANOVA (eg, normality) were assessed, and, if necessary, the data were transformed.

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Conclusion générale des auteurs In conclusion, serum concentrations of infliximab 16 weeks after switching to CT-P13 were non-inferior to those at baseline in patients with stable ulcerative colitis and Crohn’s disease. Switching patients with inflammatory bowel disease who are in clinical remission to CT-P13 is efficacious and well tolerated.

Financement de l’étude The study funder (Mundipharma) was responsible for study design, the study protocol, and data monitoring, funded the analysis of the blood samples done by independent laboratories and the statistical analyses done by an independent statistician, and was involved in data interpretation and in writing of the report.

Déclaration des conflits d’intérêts ASS has received lecture fees from Merck Sharp & Dohme, Takeda, AbbVie, Tillots, Pfizer, and Mundipharma. PJJB has received educational grants from AbbVie and Janssen, speaker fees from AbbVie and Takeda, and advisory board fees from Hospira, Janssen, Merck Sharp & Dohme, Mundipharma, Roche, Pfizer, Takeda, and Dr Falk Benelux. MN has received institutional research support consultancy fees, or speaker fees from Pfizer, Abbvie, Roche, Bristol-Myers Squibb, Merck Sharp & Dohme, Mundipharma, UCB, Janssen, Menarini, Eli Lilly, Celgene, and Abbvie. TR has received honoraria for lectures from Pfizer, Abbvie, and Regeneron, and a research grant from Genmab. GRD has served as adviser for Abbvie, Ablynx, Amakem, AM Pharma, Avaxia, Biogen, Bristol-Myers Squibb, Boerhinger Ingelheim, Celgene, Celltrion, Cosmo, Covidien, Ferring, Dr Falk, Engene, Galapagos, Gilead, GlaxoSmithKline, Hospira, Immunic, Johnson & Johnson, Lycera, Medimetrics, Millennium, Takeda, Mitsubishi Pharma, Merck Sharp & Dohme, Mundipharma, Novonordisk, Pfizer, Prometheus Laboratories, Nestlé, Protagonist, Receptos, Robarts Clinical Trials, Salix, Sandoz, Setpoint, Shire, Teva, Tigenix, Tillotts, Topivert, Versant, and Vifor, and received speaker fees from Abbvie, Ferring, Johnson & Johnson, Merck Sharp & Dohme, Mundipharma, Norgine, Pfizer, Shire, Millenium, Takeda, Tillotts, and Vifor. JPJB-M and YJBvM are employees of Mundipharma. All other authors declare no competing interests.

Approbation éthique This trial was done according to the Declaration of Helsinki. The study protocol was approved by the ethics committees of all 13 study sites.


Tableau D64 – Caractéristiques de Tanaka 2016

Auteur, année Tanaka et ses collaborateurs, 2016

Essai clinique Nom (no) JapicCTI-142419

Phase extention


S.O.

Titre Safety and efficacy of CT-P13 in Japanese patients with rheumatoid arthritis in an extension phase or after switching from infliximab

Objectif This study aimed to evaluate the safety of CT-P13 in patients with rheumatoid arthritis (RA) during long-term treatment or after switching from innovator infliximab (IFX).

Devis et méthode ECRA extension study. open-label, single-arm, multicenter,


BR/BS n = 33 BS/BS n =38

Critères inclusion

Patients who underwent the last observation after 54 weeks of treatment and were clinically stable at the last visit of the phase I/II study Patients who were judged to be suitable by the investigators for treatment with CT-P13 at the time of completion of the last observation after 54weeks of treatment in the phase I/II study Patients who were able to comply with the extension study protocol Patients who signed and dated the written informed consent form for participation in the extension study Females who experienced their last period more than one year prior to study entry. Both male and female patients and their partners of childbearing potential who had agreed to use more than 2 methods of contraception, as described below, from study entry to 6 months after discontinuation of study treatments Barrier contraceptives (male condom, female condom, or diaphragm with spermicidal gel) Hormonal contraceptives (implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings) Intrauterine devices

141


Male or female patients and their partners who had been surgically sterilized for less than 6 months prior to study entry had agreed to use 2 medically accepted methods of contraception as per inclusion criterion 5 Patients who met the following criteria via the screening laboratory tests Serum creatinine < 1.7 × upper limit of normal (ULN) Serum alanine aminotransferase (ALT) and Serum aspartate aminotransferase (AST) < 2 × ULN Hemoglobin ≥8.0 g/dL White blood cell count ≥4.0 × 103 cells/μL Neutrophil count ≥1.5 × 103 cells/μL Lymphocyte count≥1.0 × 103 cells/μL Platelet count ≥100 × 103 cells/μL Blood β-D-glucan negative Patients who were receiving oral glucocorticoids less than or equivalent to ≤10 mg daily of Prednisolone at the time of study entry. However, patients were permitted to receive topical, otological, and ophthalmic glucocorticoid preparations.

Critères exclusion

Exclusion criteria Patients who had clinical indications of a deterioration of RA disease as compared with the disease status at the study entry of Phase I/II study Patients who received a live or live-attenuated vaccination during Phase I/II study or who were scheduled to receive a live or live-attenuated vaccination during the period of this study Patients who had a current infection with hepatitis B, hepatitis C or HIV at the time of study entry. Patients who had a positive result to the screening test for HIV antibody, HBs antigen, HBc antibody or HCV antibody Patients who had a current diagnosis of TB or nontuberculous mycobacterial infection at the time of study entry Patients who had a current diagnosis of serious infection (such as sepsis, abscess or opportunistic infections, or invasive fungal infection such as histoplasmosis) at the time of study entry Patients who had recent exposure to persons with active TB at the time of study entry, or who had a positive result to the screening test for latent TB defined as a positive result of interferon-γ release assay and who was not enable to receive Isoniazid therapy Patients who had a current diagnosis of drug or alcohol abuse Patients who had a medical condition including one or more of the following: Bone marrow hypoplasia Severe or uncontrolled diabetes mellitus Any other inflammatory or rheumatic diseases, including but not limited to psoriatic arthritis, AS, spondyloarthritis, systemic lupus erythematosus, Lyme disease, or fibromyalgia, that could confound the evaluation of the effect of study treatment Malignancy Congestive heart failure (New York Heart Association class III/IV) or angina (Canadian Cardiovascular Society class III/IV) Organ transplantation Class IV of Steinbrocker classification at the time of study entry Any clinically significant respiratory disease, including but not limited to chronic obstructive pulmonary disease, asthma, bronchiectasis, or pleural effusion, and deteriorated during Phase I/II study New diagnosis or exacerbation of interstitial pneumonitis during phase I/II study Diagnosis or symptoms suggestive of demyelinating disorders, including multiple sclerosis and Guillain-Barré syndrome Nervous system damage, if it might interfere with the investigator’s assessment Female patients who were currently pregnant or breastfeeding Patients who, in the opinion of principal- or sub-investigator, should not participate in the study.

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Intervention Switch from Infliximab to CT-P13

Comparateur S.O.


Principal Safety parameters including adverse events (AEs), serious AEs (SAEs), vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, and body temperature), physical findings, laboratory test results, infections (including tuberculosis), and infusion-related reactions were assessed at each visit, and anti-drug antibodies (ADA), proportion of patients whose interferon-gamma (INF-g) release assay result became positive, and electrocardiogram findings were assessed at 24-week intervals. Serum samples for analysis were collected before each dose of CT-P13. Serum ADAs were analyzed by electroluminescence assay using the Meso Scale Discovery platform (MSD, Rockville, MD). This ADA assay system was able to detect both anti-IFX and anti-CTP13 antibodies

Secondaires Efficacy parameters were assessed at 24-week intervals. These parameters included the American College of Rheumatology 20%, 50%, and 70% response rates (ACR20, ACR50, ACR70) [5,6], changes from baseline in disease activity score using a 28-joint count (DAS28) [7], the proportions of patients achieving moderate or good response according to the European League Against Rheumatism (EULAR) response criteria [8], simplified disease activity index (SDAI) [9], clinical disease activity index (CDAI) [10], and Health Assessment Questionnaire disability index (HAQ-DI)

Milieu de dispensation des soins 20 medical institutions throughout Japan,

Durée du suivi 54 weeks, between December 2012 and February 2015,


Puissance N.D.

Type N.D.

Test All patients who received at least one dose of CT-P13 in the extension study were included in the safety analysis set. All AEs occurring between the start of study treatment and the time of assessment for the completion or discontinuation of study treatment were documented. The data were summarized in terms of the number of AEs, the number and percentage of patients experiencing each AE, as well as severity and relation to the study drug both in patients enrolled from the CT-P13 group of the phase I/II study (the maintenance group) and from the IFX group (the switch group). For laboratory parameters, the observed value and the changes from the value obtained immediately before the first study treatment at the phase I/II study (baseline) were summarized using descriptive statistics. Data on ADA are expressed in terms of the proportion of ADA-positive patients. Efficacy analyses were performed on the full analysis set (FAS), which consisted of all patients who were eligible for the extension study and received at least one dose of the study drug. Patients who were ineligible for the phase I/II study were excluded from the FAS. For efficacy parameters, observed values and changes from baseline were summarized using descriptive statistics for each group. The non-responder imputation (NRI) procedure was applied for patients who were withdrawn due to insufficient response or adverse reactions, whereby missing continuous data were imputed by baseline data. Missing data generated due to other reasons were imputed using the last observation carried forward (LOCF) method.

143


Conclusion générale des auteurs In summary, CT-P13 was generally well tolerated with persistent efficacy for RA during the long-term treatment over 54 weeks as well as after the switch to CT-P13 from IFX treatment after 54 weeks. AEs observed in the long-term treatment included malignant tumor, infusion-related reactions in ADA-positive patients and infectious diseases in dose-increased patients.


Déclaration des conflits d’intérêts Y.T. has received grants, personal fees, and non-financial support from Nippon Kayaku Co., Ltd. during this study, personal fees from Nippon Kayaku Co., Ltd., and grants from Mitsubishi Tanabe Pharma Corp., Takeda Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Eisai Co., Ltd., Taisho Toyama Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., AbbVie GK, and Bristol-Myers K.K. outside the submitted work. H.Y. has received grants and personal fees from Nippon Kayaku Co., Ltd. during this study, and personal fees from Nippon Kayaku Co., Ltd. outside the submitted work. T.T. has received grants, personal fees, and non-financial support from Nippon Kayaku Co., Ltd., AbbVie GK, Bristol- Myers K.K., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd. and Mitsubishi Tanabe Pharma Corp., grants and non-financial support from Daiichi Sankyo Co., Ltd., personal fees from Pfizer Japan Inc., grants from Takeda Pharmaceutical Co., Ltd. during this study; grants, personal fees, and non-financial support from Astellas Pharma Inc., and grants from Santen Pharmaceutical Co., Ltd., Teijin Pharma Ltd., Asahi Kasei Pharma Corp., Taisho Toyama Pharmaceutical Co., Ltd. and SymBio Pharmaceuticals Ltd. outside the submitted work. M.I. has received grants and non-financial support from Nippon Kayaku Co., Ltd. during the conduct of the study; and personal fees from Nippon Kayaku Co., Ltd. outside the submitted work. K.S. has received grants and non-financial support from Nippon Kayaku Co., Ltd. during this study. Y.S. has received grants and non-financial support from Nippon Kayaku Co., Ltd. during this study. S.J.L. is a full-time employee of Celltrion, Inc. and has received personal fees and non-financial support from Celltrion, Inc. during this study, as well as personal fees and non-financial support from Celltrion, Inc. outside the submitted work. Y.N. is a board member with stock ownership of Nippon Kayaku Co., Ltd., and has received personal fees and non-financial support from Nippon Kayaku Co., Ltd. during this study, as well as personal fees and non-financial support from Nippon Kayaku Co., Ltd. outside the submitted work.

Approbation éthique This study was conducted in accordance with the ethical principles derived from the Declaration of Helsinki, and in compliance with the Good Clinical Practice guidelines. The study protocol and informed consent form were reviewed and approved by the Institutional Review Board at each site. Written informed consent was obtained from all patients.


Tableau D65 – Caractéristiques de Thadhani 2018

Auteur, année Thadhani et ses collaborateurs, 2018

Essai clinique

Nom (no) PIEDA study (NCT02504294)

Phase 3


After the commencement of the study, the exclusion criteria were revised to provide clarity on permitted anti-platelet therapy and the use of heparin during hemodialysis, as well as criteria for management of patients on warfarin therapy. This endpoint was introduced in a protocol amendment in December 2015, after the commencement of the study; the original primary endpoint was the proportion of patients who maintained a mean hemoglobin level within the target range during the final 8 weeks of the study. The modification was introduced to allow continuous rather than categorical assessment of data, and hence provide similar statistical power to the initial design but with a smaller sample size. Accordingly, the planned statistical analysis of the primary endpoint (detailed below) was also updated.

Titre Switching from epoetin alfa (Epogen®) to epoetin alfa-epbx (RetacritTM) using a specified dosing algorithm: A randomized, non-inferiority study in adults on hemodialysis

Objectif We conducted the PIEDA study (A Phase 3b Investigation of Erythropoietin Drugs Using a Specified Dosing Algorithm) with the primary objective of investigating how switching from Epogen® reference product (the standard-of-care treatment) to Retacrit™ affects the maintenance of hemoglobin levels in patients on hemodialysis when using a specified ESA-dosing algorithm

Devis et méthode ECRA prospective, randomized, open label

144



N= 432 BR/BR n= 211 BR/BS n=221

Critères inclusion

Patients were adults (≥18 years old) with anemia and CKD who had been receiving in-center hemodialysis for ≥120 days. Patients needed to be stable on treatment with Epogen®, defined as having received routine IV Epogen® for treatment of anemia for ≥16 weeks and not having missed more than 3 prescribed doses within the 12 weeks before randomization. Patients had to be currently using the IV Epogen® version of the FMCNA ESA-dosing algorithm for anemia management and be receiving hemodialysis at a clinic using the FMCNA dosing algorithm for IV iron

Critères exclusion

Female patients were excluded if they were pregnant or lactating or were of childbearing potential but did not agree to use a highly effective method of contraception as determined by the investigator. Patients were also excluded if they had any concurrent condition that could lead to greater-than-normal loss of blood, as were those with a history of transfusion of any blood product in the past 3 months, with 2 or more transfusions in the past year, or who had donated or lost > 475 mL blood volume (including plasmapheresis) in the past 3 months. Patients who were receiving a long-acting ESA or who had received a long-acting ESA in the 16 weeks before study randomization were also excluded. After the commencement of the study, the exclusion criteria were revised to provide clarity on permitted anti-platelet therapy and the use of heparin during hemodialysis, as well as criteria for management of patients on warfarin therapy.


Intervention BR/BS Switch from Epogen® to Retacrit™

Comparateur BR/BR standard-of-care, continue treatment with Epogen®


Principal The primary efficacy endpoint was the proportion of time patients’ hemoglobin levels were 9–11 g/dL during the final 8 weeks of the study (weeks 17–24).

Secondaires The secondary efficacy endpoint was the change from baseline in the mean ESA dose per patient per week over the final 8 weeks of the study, with baseline defined as the mean ESA dose per patient per week during the 8 weeks prior to randomization. Additionally, pre-specified exploratory analyses were performed to compare variables such as TSAT levels, ferritin levels, and IV iron dosing requirements associated with use

145


of RetacritTM and Epogen®, in addition to other hemoglobin-level comparisons. With the exception of the percentage of patients with mean hemoglobin levels in specific ranges over the final 8 weeks of the study, exploratory endpoints are not reported here.

Milieu de dispensation des soins 46 facilities in United-States and Puerto Rico

Durée du suivi 24 weeks July 2015 to July 2016


Puissance Non-inferiority was considered demonstrated if the lower bound of the 95% CI for the difference in proportions was greater than the non-inferiority margin of –12.5%. This margin was selected as it was considered by the study team to represent a clinically meaningful difference between the groups. Assuming an SD of 28%, a true difference between the groups of 0, and a 70% evaluable rate, 378 randomized patients were required to provide approximately 90% power to demonstrate non-inferiority.

Type per protocol

Test For the primary endpoint, the proportion of time a patient’s hemoglobin level was 9–11 g/dL over the final 8 weeks of the study was calculated using the number of hemoglobin measurements that were within the target range during weeks 17–24 as the numerator and the total number of hemoglobin measurements during weeks 17–24 as the denominator. A clustered binomial analysis using the logistic regression method was performed on binary response data to compare the proportions of time hemoglobin levels were within the target range in each treatment arm. Patients’ baseline hemoglobin levels were included as a covariate. The generalized estimating equation method was used to construct 95% CIs of the proportions and of the difference in proportions. The secondary endpoint was evaluated using an analysis of covariance model with treatment as a factor and mean ESA dose per week over the 8-week period before randomization as a covariate. The least-squares mean, SE, and least-squares mean difference between the treatment arms, along with the 95% CI of the difference between them, were obtained. Missing assessments and missing data were not imputed. For the RetacritTM and standard-of-care arms, the full analysis set (FAS) comprised all patients who received at least one dose of RetacritTM or Epogen® after randomization, respectively. For analysis of a particular variable, a patient had to have at least one measurement in the defined visit to be included. The primary analysis of the primary endpoint was performed on the FAS; for this endpoint, a patient was required to have at least one valid value during the final 8 weeks of the study to be included. The per protocol set comprised patients who completed the final 8 weeks of treatment and did not miss more than 3 defined and scheduled doses of the ESA to which they were randomized during the final 8-week period. Patients who received a dose of the treatment other than that to which they were randomized during the final 8 weeks were excluded from per protocol set. Patients who were scheduled to have their ESA dose(s) held or interrupted according to the dosing algorithm were not considered to have missed doses. Efficacy and safety summaries and analyses were performed on FAS data. Additional efficacy analyses were performed in the per protocol set. In the efficacy analysis, patients were analyzed in the group according to the treatment assigned at randomization. In the safety analysis, patients were analyzed in the group according to the treatment received.


In conclusion, in the current study, switching to the epoetin alfa biosimilar RetacritTM was found to be noninferior to continued treatment with Epogen® reference product in maintaining hemoglobin levels in patients with anemia and CKD managed on hemodialysis, when both treatments were dosed using a specified algorithm.

Financement de l’étude This study was sponsored by Hospira Inc, which was acquired by Pfizer in September 2015. The sponsor was involved in study design, study conduct, and data analysis. Additionally, employees of the sponsor contributed to manuscript preparation (see the Author Contribution statement).


R.T. is a consultant to FMCNA and has received honoraria from Pfizer for participating in advisory boards. R.G. is an employee of Pfizer. J.H. and F.W.M. are employed by Fresenius Medical Care. A.A. was an employee of Pfizer at the time of study conduct.

Approbation éthique The study was conducted in accordance with the Declaration of Helsinki and all local regulatory requirements. Patients were required to give informed consent before any screening procedures were carried out. The final protocol, its amendments, and informed consent documentation were reviewed and approved by the central and local institutional review boards at each of the participating centers.


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Tableau D66 – Caractéristiques de Tony 2019

Auteur, année Tony et ses collaborateurs, 2019

Essai clinique


Phase N.D.


N.D.

Titre Brief report: Safety and immunogenicity of rituximab biosimilar GP 2013 after switch from reference rituximab in patients with active rheumatoid arthritis

Objectif Comparable clinical efficacy of the rituximab (RTX) biosimilar GP2013 and reference RTX has been established in blinded randomized trials. However, when switching from a reference biologic to a biosimilar, potential safety implications are often an important consideration. Therefore, the aim of this study was to evaluate the safety of switching from reference RTX to RTX biosimilar GP2013 compared with treatment continuation with reference RTX in patients with rheumatoid arthritis (RA).

Devis et méthode ECRA randomized, double-blind, parallel-group safety study,


N= 107 BR/BS n= 53 BR/BR n= 54

Critères inclusion

The study population consisted of adult patients with RA who had previously received RTX as part of routine practice and who required continuation of RTX treatment according to the judgment of the consulting rheumatologist. There was no limitation regarding the duration of previous RTX treatment. Male patients, or non-pregnant, non-lactating female patients, at least 18 years of age at screening, who provided written informed consent before any assessment was performed. • Rheumatoid arthritis according to American College of Rheumatology [ACR] 2010 criteria. • At least one full treatment course of reference rituximab for the therapy of rheumatoid arthritis, 6 to 18 months prior to randomization. • Eligible for a subsequent treatment course of rituximab according to the clinical judgment of the investigator. • Stable dose of methotrexate and folic acid for at least 4 weeks prior to randomization.

Critères exclusion

• RA functional status class IV (ACR 1991 revised criteria) • Treatment with any biologics for any indication since the start of last treatment with rituximab • History of severe hypersensitivity to rituximab, which required drug discontinuation • Previously treated with any cell depleting therapies, including investigational agents • Known severely immunocompromised state • Active systemic infection • Immunoglobulins below lower limit of normal (LLN) • Positive serology for hepatitis B or hepatitis C infection • History of cancer

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Intervention BS : GP2013 to receive two 1,000-mg intravenous infusions of biosimilar GP2013. Two intravenous infusions of study medication were administered at investigational sites on 2 consecutive visits 2 weeks apart, with intravenous methylprednisolone, antipyretic, and antihistamine premedication given prior to each infusion. All patients received a stable dosage of methotrexate (7.5–25 mg/week) and folic acid during the study.

Comparateur BR: rituximab (RTX) to receive two 1,000-mg intravenous infusions of reference RTX (sourced from either the European Union or the US as received prior to study enrollment). Two intravenous infusions of study medication were administered at investigational sites on 2 consecutive visits 2 weeks apart, with intravenous methylprednisolone, antipyretic, and antihistamine premedication given prior to each infusion. All patients received a stable dosage of methotrexate (7.5–25 mg/week) and folic acid during the study.


Principal Safety

Secondaires S.O.

Milieu de dispensation des soins 54 centers across 4 countries (US, Germany, Poland, and Hungary)

Durée du suivi 24 semaines; July 2015 October 2016


Puissance Due to the known low incidence of investigated key safety end points after RTX treatment in patients with RA, a prohibitively large sample size would be required to perform fully powered hypothesis testing for equivalence. Therefore, the sample size in this study was not based on statistical considerations.

Type N.D.

Test Descriptive statistics were used for all safety end points; point estimates and 95% confidence intervals (95% CIs) were calculated for differences in the incidence rates of key safety end points between treatment arms. Given the small sample size and low event rate observed in this study, the 95% CIs were estimated using the most

148


conservative approach, based on the exact unconditional method With a sample size of 100 patients (50 patients per treatment group), the expected upper limits of the 95% CIs for the incidence differences between treatment groups were 10.3% for hypersensitivity, 3.9% for anaphylaxis, 17.0% for infusion-related reactions, and 11.2% for the incidence of antidrug antibodies. In the safety analysis, any difference between treatment groups that exceeded the respective upper limit value would be considered a statistically significant signal of potential difference in the specific end point. Calculations were based on the assumption that no difference would be observed between treatment groups, and based on the incidences of safety end points as observed both in previous literature or in prior studies of GP2013: hypersensitivity, 7.5%; anaphylaxis, 1%; infusion-related reactions, 17.0%; and immunogenicity, 9%.


In summary, the results of this study demonstrate that treatment switch from reference RTX to the biosimilar GP2013 in RA patients previously treated with RTX as part of routine practice has a safety profile comparable to continuation of reference RTX. No additional safety risks were detected in patients who switched from reference RTX to GP2013.

Financement de l’étude Supported by Hexal AG, a Sandoz Company (all countries except the US) and by Sandoz (US). Sandoz is a division of Novartis. Sandoz facilitated the study design, provided writing assistance for the manuscript, and reviewed and approved the manuscript prior to submission. The authors independently collected the data, interpreted the results, and had the final decision to submit the manuscript for publication. Editorial assistance was provided by Ben Caldwell (Spirit, Manchester, UK) and funded by Hexal AG, a Sandoz company. Publication of this article was not contingent upon approval by Sandoz.


Dr. Tony has received speaking fees and/or honoraria from AbbVie, AstraZeneca, Chugai, Janssen-Cilag, Lilly, Novartis, Roche, Hexal (a Sandoz Company), and Sandoz (less than $10,000 each). Dr. Krüger has received speaking fees and consulting fees (less than $10,000 each) and research support from Hexal (a Sandoz Company) and Novartis. Dr. Cohen has received consulting fees from Sandoz (less than $10,000). Dr. Schulze- Koops has received consulting fees from Novartis and Roche (more than $10,000 each) and Sandoz (less than $10,000). Alan Kivitz has received consulting fees from AbbVie, Amgen, Celgene, Genentech, Genzyme, Horizon, Janssen, Merck, UCB, Vertex, SUN Pharma Advanced Research (less than $10,000 each) and Novartis, Pfizer, Regeneron, and Sanofi (more than $10,000 each).



Tableau D67 – Caractéristiques de Tweehuysen 2018a

Auteur, année Tweehuysen et ses collaborateurs, 2018

Essai clinique

Nom (no) BIO-SPAN study

Phase N.D.


N.D.

Titre Open-label, non-mandatory transitioning from originator etanercept to biosimilar SB4: Six-month results from a controlled cohort study

Objectif To evaluate the effects of non-mandatory transitioning from the originator biologic drug etanercept (ETN) to its biosimilar, SB4, on drug survival and effectiveness in a controlled cohort study of patients with an inflammatory rheumatic disease.

Devis et méthode ECRNA comparé à une cohorte historique

Population

Nombre sujets inclus

N= 1225 BR/BS n= 625 BR n= 600

Critères inclusion

Patients ages ≥18 years who had a clinical diagnosis of either RA, PsA, or AS and who had agreed to transition to SB4 were eligible for inclusion in the transition cohort.

Critères exclusion

N.D.

149



Intervention BR/BS Adult patients who were being treated with originator ETN (Enbrel®) (50 mg in a prefilled pen or syringe) were informed by letter about the option to transition to the biosimilar SB4. SB4 was prescribed in the same dosage, interval, and device (pen or syringe) as that for the originator ETN.

Comparateur BR treated with originator ETN in the same hospital in June 2014.


Principal The primary outcome was the adjusted hazard ratio (HR) for the risk of treatment discontinuation in the biosimilar SB4 transition cohort relative to the originator ETN historical cohort.

Secondaires Secondary outcomes included reasons for SB4 or ETN discontinuation, prediction of SB4 discontinuation, and differences in disease activity measurements over 6months. Reasons for SB4 or ETN discontinuation were documented

Milieu de dispensation des soins the Sint Maartenskliniek in Nijmegen, The Netherlands



Puissance N.D.

Type intent-to treat

Test Descriptive statistics are expressed as the mean ± SD, median (interquartile range [IQR]), or frequency, depending on the distribution of the data. Baseline characteristics were compared using Student’s t-test (or, if not normally distributed, Wilcoxon’s rank sum test) and chi-square test for continuous and categorical data, respectively. Data from the included questionnaires were analyzed according to previously published methods (18,19,21,25). Treatment persistence was compared between the biosimilar SB4 transition cohort and the originator ETN historical cohort. Patients who discontinued SB4 or ETN treatment because they achieved clinical remission were not coded for an event but were censored at the time of discontinuation. Since patients in the transition cohort and historical cohort might not have been comparable at baseline in terms of factors that could influence treatment persistence, a multivariate Cox regression analysis was used to adjust the HR of treatment discontinuation for differences in potential baseline confounders (i.e., age, sex, diagnosis, ETN treatment duration, ETN dose interval, concomitant conventional synthetic DMARD [csDMARD] use [yes versus no], and CRP level). As more discontinuation was expected in the first year of ETN use, ETN treatment duration was modeled both as a categorical variable (<0.5 years versus 0.5–1 year versus > 1 year) and as a continuous variable (in which year 1 was recoded as 0, and after that, as year minus 1). A robust variance estimator was applied in the Cox regression to account for repeated subjects (i.e., patients included in both the transition cohort and the historical cohort). In the transition cohort, univariate Cox regression analyses of groups stratified by diagnosis were performed to assess whether baseline

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characteristics were associated with SB4 discontinuation. Variables that showed an association with SB4 discontinuation (P < 0.10) in the univariate analyses were entered in the multivariate Cox regression, using stepwise backwards selection. Persistence of SB4 treatment among patients who completed the questionnaires, patients who declined to fill in the questionnaires, and patients who were not selected to fill in the questionnaires was explored with a log-rank test. In the subgroup of patients who completed questionnaires, univariate Cox regression analyses were performed to assess whether the outcomes reported on the questionnaires were associated with SB4 discontinuation. Effectiveness analyses were performed on the intent-to treat population. In the transition cohort, the CRP level, DAS28-CRP, and BASDAI scores at baseline compared to month 6 were analyzed using Wilcoxon’s signed-rank test. Linear regression analyses were performed to assess differences in the change from baseline in the CRP level, DAS28-CRP, and BASDAI score over 6 months between the transition cohort and the historical cohort. Missing values for the CRP level, DAS28-CRP, and BASDAI at baseline and at month 6 were addressed using multiple imputation, in which study cohort (transition cohort versus historical cohort), age, sex, disease duration, ETN treatment duration, ETN dose interval, and concomitant csDMARD use (yes versus no) were considered as predictors of missing values. The number of imputations was set at 10. With this complete data set, the change from baseline in CRP level, DAS28-CRP, and BASDAI score at month 6 (Δ month 6; calculated as month 6 value minus baseline value) was generated. The difference in Δ month 6 CRP level, DAS28-CRP, and BASDAI score between the transition cohort and the historical cohort was adjusted for potential confounders (baseline values for CRP, DAS28-CRP, or BASDAI, age, sex, disease duration, ETN treatment duration, ETN dose interval, and concomitant csDMARD use [yes versus no]), and a robust variance estimator was applied to account for repeated subjects. P values less than 0.05 were considered significant. All analyses were performed using Stata statistical software, version 13.1 (StataCorp).


In conclusion, non-mandatory transitioning from originator ETN to biosimilar SB4 using a specifically designed communication strategy resulted in a slightly lower SB4 treatment persistence rate and smaller decreases in disease activity compared to that in a historical cohort of patients who continued treatment with originator ETN, but these differences were not considered to be clinically relevant. Furthermore, the rates of acceptance and treatment persistence for SB4 in our transition cohort were similar to those observed after mandatory transitioning. Since mandatory transitioning to a biosimilar is not acceptable in many countries, the use of a communication strategy that might optimize acceptance and persistence rates through non-mandatory transitioning seems attractive.

Financement de l’étude The BIO-SPAN study is an investigator-initiated trial and was funded by Biogen.


Dr. van den Bemt has received speaking fees from Pfizer, AbbVie, Sandoz, and UCB (less than $10,000 each). Dr. van den Hoogen has received consulting fees and/or speaking fees from Celltrion, Sandoz, Mundipharma, Biogen, Janssen, and Egis (less than $10,000 each). Dr. den Broeder has received consulting fees and/or speaking fees from Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer (less than $10,000 each) and research support from CZ Pharma, Menzis, and ZonMw.

Approbation éthique It was judged by the local ethics committee (CMO region of Arnhem-Nijmegen) that no ethics approval was required (file no. 2016-2612),


Tableau D68 – Caractéristiques de Tweehuysen 2018b


Essai clinique

Nom (no) BIO-SWITCH study

Phase N.D.


N.D.

Titre Subjective complaints as the main reason for biosimilar discontinuation after open-label transition from reference infliximab to biosimilar infliximab

Objectif To evaluate drug survival, effectiveness, pharmacokinetics, immunogenicity, and safety in daily practice after transitioning treatment from original reference infliximab (Remicade® [REM]) to a biosimilar infliximab (CT-P13 [Remsima®; Inflectra®]) in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis.

Devis et méthode prospective cohort study July 2015, and the last 6-month evaluation was performed in May 2016.

151



N= 211 BR/BS n= 192 BR/BR n= 19

Critères inclusion

Patients ≥18 years of age with a clinical diagnosis of either RA, PsA, or AS who agreed (transition group) or did not agree (control group) to transition to CT-P13 were both eligible for inclusion in the BIO-SWITCH study.

Critères exclusion

Did not give consent


Intervention BR/BS (Remicade® [REM]) to a biosimilar infliximab (CT-P13 [Remsima®; Inflectra®]). CTP13 was administered open label at the same dosage and interval as REM.

Comparateur BR Remicade®


Principal The primary outcome measure was change in disease activity at month 6 (±2 months) relative to baseline. Disease activity in RA and PsA patients was measured with the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) and its individual components. Disease activity in AS patients was measured with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)

Secondaires Secondary outcome measures included the CRP level, the erythrocyte sedimentation rate (ESR), infliximab trough levels, anti-infliximab antibody levels, and safety. At baseline and at the 6-month follow-up.

Milieu de dispensation des soins 4 rheumatology departments in The Netherlands: St. Maartenskliniek Nijmegen, Maartenskliniek Woerden, Radboud University Medical Center Nijmegen, and Rijnstate Arnhem.



Puissance N.D.

Type N.D.

Test All analyses were performed with STATA 13.1 statistical software (StataCorp). Descriptive statistics are reported as either the mean ± SD, the median and interquartile range (IQR), or the frequency, depending on data distribution. A Kaplan-Meier curve was plotted to depict survival of patients receiving CT-P13 over 6 months. Primary effectiveness analyses were performed on the intent-to-treat population. We intended that non transitioning patients would be a quasi-experimental control group. However, due to the high acceptance rate for transitioning (n = 192), the control group was too small (n = 19). Differences between continuous variables at baseline versus 6 months were analyzed using paired t-test or Wilcoxon’s signed rank test, depending on distribution. For the pharmacokinetics and immunogenicity analyses, only patients with available samples at baseline and at month 6 who were still taking infliximab (REM or CT-P13) were included. AEs were reported as the cumulative incidence and the incidence density per 100 patient-years. In patients who discontinued treatment, AEs that were reported up to the restart of REM or any other biologic drug or up to day 38

152


after the last dose of CT-P13 (>4 times the half-life of 9.5 days) were included. To identify independent predictors of CT-P13 discontinuation, patient-specific, disease-specific, and treatment-specific variables that showed an association (P < 0.10) with discontinuation of CT-P13 in the univariate analyses were entered in a multivariate Cox regression analysis using a backward elimination procedure with the lowest Akaike information criterion as selection criterion.


All things considered, the substantial discontinuation rate of CT-P13 due to subjective health complaints after open-label transitioning might be explained by nocebo and/or incorrect causal attribution effects. As a result, communication seems to be the determining factor of the success of transitioning to a biosimilar drug in daily practice.

Financement de l’étude The BIO-SPAN study is an investigator-initiated trial and was funded by Biogen.


Dr. van den Bemt has received speaking fees from Pfizer, AbbVie, Sandoz, and UCB (less than $10,000 each). Dr. van den Hoogen has received consulting fees and/or speaking fees from Biogen, Celltrion, Janssen, Mundipharma, Sandoz, and Egis (less than $10,000 each). Dr. den Broeder has received consulting fees and/or speaking fees from Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer (less than $10,000 each).

Approbation éthique It was approved by the local ethics committee (CMO region Arnhem-Nijmegen)


Tableau D69 – Caractéristiques de Van Hoeve 2019

Auteur, année Van Hoeve et ses collaborateurs, 2019


Phase N.D.


N.D.

Titre Efficacy, pharmacokinetics and immunogenicity is not affected by switching from infliximab originator to a biosimilar in pediatric patients with inflammatory bowel disease

Objectif Therefore, the aim of this study was to evaluate the long-term changes in IFX trough levels, immunogenicity, and remission rates after switching from the IFX originator to the biosimilar CT-P13 in pediatric patients with IBD during maintenance therapy.

Devis et méthode A prospective, observational study


Forty-seven of them received maintenance therapy with the originator Remicade® for at least 4 months. Forty-two of them were eligible for the study. CD was diagnosed in 26 patients (61.9%) and UC in 16 patients (38.1%).

Critères inclusion

Pediatric patients who received maintenance IFX therapy between July 2017 and January 2018. Eligible subjects were patients who had been receiving the originator Remicade® for at least 4 months (to receive at least one maintenance infusion of the IFX originator before switch).

Critères exclusion

N.D.


Intervention CT-P13

153

Auteur, année Van Hoeve et ses collaborateurs, 2019

Comparateur Infliximab BR (Remicade®)


Principal The primary aim of this study was to evaluate whether there was a significant difference between IFX trough levels and/or ATIs after switching to the biosimilar CT-P13 during a total period of 1 year.

Secondaires The secondary aim was to evaluate whether the proportion of patients in clinical and/or biological remission was similar before and after switching to CT-P13.

Milieu de dispensation des soins Tertiary referral center for the treatment of active Crohn disease (CD) or ulcerative colitis (UC).

Durée du suivi 1 year (6 months before until 6 months after switching to CT-P13).


Puissance N.D.

Type Continuous variables were presented as medians with interquartile ranges. Categorical variables were presented as frequencies and percentages.

Test For statistical comparison of paired data obtained at the different timepoints, a Wilcoxon signed rank-sum test and a Friedman test were used for continuous variables. A McNemar test was used for paired dichotomous variables. A two one-sided test of equivalence for paired samples was performed to evaluate the similarities between the average cumulative IFX dose before and after switching to the biosimilar CT-P13, where the equivalence margin was set at d = 30% points. For this analysis, the 90% confidence interval of the mean values between the 2 products fell within the range from 70% to 130%, then the products were considered equivalent. P values were calculated 2-tailed, and the threshold for significance was set at 0.05.

Conclusion générale des auteurs In conclusion, we have demonstrated that pediatric patients with IBD can be successfully switched during maintenance from the originator to the biosimilar CT-P13. At 6-month follow-up, there was no significant difference with respect to efficacy, pharmacokinetics, immunogenicity, or other patients’ covariates.

Financement de l’étude K. van Hoeve reports having received research grant from Mundipharma Comm. VA and Celltrion Healthcare Co. G. Van Assche, M. Ferrante and S. Vermeire are senior clinical investigators of the Research Foundation-Flanders (FWO).

Déclaration des conflits d’intérêts K. van Hoeve: Research grant: Mundipharma Comm. VA and Celltrion Healthcare Co. I. Hoffman: Lecture fees: Nutrica, nestlé, Mead Johnson, Abbvie; G. Van Acche: Research grant: Abbvie, Pfizer; Consultancy: Abbvie, MSD, Ferring, Takeda, Janssen, Pfizer Inc, Genentech/Roche; Speakers fee: AbbVie, Janssen, MSD, Takeda, Ferring, Dr. Falk Pharma, Pfizer; M. Ferrante: Research grant: Janssen, Takeda; Consultancy: AbbVie, Boehringer Ingelheim, Ferring, Janssen, Mitsubishi Tanabe, MSD, Pfizer; Speakers fee: AbbVie, Boehringer Ingelheim, Chiesi, Ferring, Janssen, Lamepro, Mitsubishi Tanabe, MSD, Pfizer, Tramedico, Tillotts, Zeria; A. Gils: Lecture fees: MSD, Janssen Biologicals, Pfizer, Takeda, Abbvie, Novartis; Advisory board: Takeda; Financial research support: Pfizer, MSD; license agreement: R-biopharm, apDia, Merck. S. Vermeire: Research grant: Takeda, MSD, Abbvie, Pfizer. Consultancy: Abbvie, MSD, Ferring, Takeda, Shire, Janssen, Pfizer Inc, Galapagos, Genentech/Roche, Celgene, Mundipharma, Eli Lilly, Second Genome, GSK; Speakers fee: AbbVie, MSD, Takeda, Ferring, Dr. Falk Pharma, Hospira, Pfizer Inc, and Tillotts. The remaining authors have no conflicts of interests to disclose.

Approbation éthique The Ethical Committee of our university hospital approved the study (Approval No: S59870, April 10, 2017).


Tableau D70 – Caractéristiques de Vergara-Dangond 2017

Auteur, année Vergara-Dangond et ses collaborateurs, 2017

Essai clinique

Nom (no) N.D.

Phase N.D.


N.D.

Titre Effectiveness and safety of switching from innovator infliximab to biosimilar CT-P13 in inflammatory rheumatic diseases: A real-world case study

Objectif CT-P13 is a biosimilar with comparable pharmacokinetics, efficacy and safety to its reference product (RP), infliximab. Studies have shown that switching from RP to CT-P13 does not reduce the effectiveness or safety of treatment.

Devis et méthode Prospective cohort

154

Auteur, année Vergara-Dangond et ses collaborateurs, 2017


N= 13 BR/BS n= 7 BR/BR n= 6

Critères inclusion

diagnosed with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) who had been treated with, and had responded to, infliximab RP

Critères exclusion

N.D.


Intervention BR/BS switched from Innovator Infliximab to Biosimilar CT-P13 Doses of study drug (i.e., CT-P13 or RP) were individually optimized during the study according to clinician judgement. Patients receiving concomitant disease-modifying antirheumatic drugs before the start of the study continued such treatment in line with clinical need.

Comparateur BR/BR Innovator Infliximab


Principal Efficacity

Secondaires Safety

Milieu de dispensation des soins 1 center in Spain

Durée du suivi Clinical response was assessed before and after four cycles of treatment: June 2015 and January 2016


Puissance N.D.

Type N.D.

Test N.D.


Switching from the RP to CT-P13 did not affect the safety or effectiveness of treatment in patients with different inflammatory diseases in this study. These findings support other data that show that CT-P13 is a valid alternative to infliximab RP in patients requiring anti-TNF therapy. Replacing innovator biologics with more cost-effective biosimilars will likely expand access to these effective treatments and ensure that increased numbers of patients can benefit.

Financement de l’étude Medical writing support was funded by CELLTRION Healthcare Co., Ltd. No other funding was provided for this study.


CV-D, MSB, MCM, PLS, and JJA-S declare that they have no conflicts of interest.

Approbation éthique The study was conducted according to the principles of the Declaration of Helsinki.


155

Tableau D71 – Caractéristiques de Von Minckwitz 2018

Auteur, année Von Minckwitz et ses collaborateurs, 2018

Essai clinique

Nom (no) LILAC study (NCT01901146 and Eudra, number CT 2012-004319-29)

Phase 3


N.D.

Titre Efficacy and safety of ABP 980 compared with reference trastuzumab in women with HER2-positive early breast cancer (LILAC study): A randomised, double-blind, phase 3 trial

Objectif We assessed the clinical similarity of ABP 980 and trastuzumab in women with HER2-positive early breast cancer in the neoadjuvant and adjuvant settings, based on the proportion of patients achieving a pathological complete response. We compared safety, tolerability, and immunogenicity, including after switching treatment from trastuzumab to ABP 980 to generate data about clinical use.

Devis et méthode ECRA phase 3 double-blind, active-controlled


N= 725 BS n= 364; BS/BS n= 349 BR n= 361; BR/BR n= 171; BR/BS n= 171

Critères inclusion

women aged 18 years or older with histologically confirmed invasive breast cancer and an Eastern Cooperative Oncology Group performance status score of 0 or 1, who were planning to have surgical resection of their breast tumour with sentinel or axillary lymph node dissection and neoadjuvant chemotherapy. Inclusion criteria were HER2-positive disease confirmed by a central laboratory before randomisation (defined as 3+ overexpression on immunohistochemistry or HER2 amplification on fluorescence in situ hybridisation), known oestrogen-receptor and progesterone-receptor status at study entry, measurable disease in the breast after diagnostic biopsy (defined as longest tumour diameter ≥2·0 cm), and left ventricular ejection fraction (LVEF) of at least 55% on a two-dimensional echocardiogram

Critères exclusion

Exclusion criteria were presence of bilateral breast cancer or known distant metastases; previous treatment for primary breast cancer, including chemotherapy, a biological agent, radiotherapy, or surgery; concomitant active malignancy; and malignant disease in the previous 5 years, except treated basal-cell carcinoma of the skin or carcinoma in situ of the cervix.


Intervention BR/BS Switch from Trastuzumab originator to biosimilar ABP 980 (Amgen Inc, Thousand Oaks, CA, USA) During the adjuvant phase, patients either continued with

156


ABP 980 or trastuzumab (dose 6 mg/kg) or switched from trastuzumab to ABP 980 6 mg/kg intravenous infusions given over 30 min every 3 weeks for up to 1 year after the first dose of neoadjuvant treatment.

Comparateur BR/BR Continue treatment with trastuzumab originator Patients received neoadjuvant therapy with a loading dose (8 mg/kg) of ABP 980 or trastuzumab plus paclitaxel 175 mg/m² in a 90 min intravenous infusion, followed by three cycles of 6 mg/kg intravenous ABP 980 or trastuzumab plus paclitaxel 175 mg/m² every 3 weeks in 30 min intravenous infusions (or 80 mg/m² paclitaxel once per week for 12 cycles if that was the local standard of care). ABP 980 or trastuzumab was given every 3 weeks for up to 1 year after the first dose in the study


Principal The co-primary efficacy endpoints were risk difference and risk ratio (RR) of pathological complete response, defined as the absence of invasive tumour cells in the breast tissue and in axillary lymph nodes regardless of ductal carcinoma in situ (as defined by the FDA).

Secondaires Secondary efficacy endpoints were risk differences and RRs for pathological complete response in breast tissue (absence of invasive tumour cells, regardless of residual ductal carcinoma in situ); risk differences and RRs for pathological complete response in breast tissue and axillary lymph nodes in the absence of ductal carcinoma in situ (defined as the absence of invasive tumour cells in breast tissue and axillary lymph nodes and absence of ductal carcinoma). Safety

Milieu de dispensation des soins 97 locations in 20 countries

Durée du suivi Up to one year; April 29, 2013, and Sept 29, 2015


Puissance The primary efficacy hypothesis was that ABP 980 would be equivalent to trastuzumab when each was given in combination with standard-of-care neoadjuvant cancer treatment (paclitaxel). The planned sample size was 808 to ensure that 768 patients (384 in each group) were randomly assigned treatment. We calculated that this number would achieve 90% power to show equivalence when assessed by RR for pathological complete response with 5% dropout during run-in chemotherapy phase. This sample size was also calculated to provide at least 90% power to show equivalence when assessed by risk difference between groups for pathological complete response with margins of -13% and 13% and a two-sided 0.05 significance level. We assumed that the proportion of patients who would achieve a pathological complete response would be approximately 42.5% in the ABP 980 and trastuzumab groups.1

Type intention-to-treat and per-protocol populations (data not shown).

Test We initially used a sequential testing method to test similarity between ABP 980 and trastuzumab by comparing the two-sided 90% CI for risk difference between the ABP 980 and trastuzumab groups with statistical margins of –13% and 13%. If the test on the risk difference was successful, similarity was then tested by RR of pathological complete response at a two-sided significance level of 0.05 by comparing the two-sided 90% CI between the ABP 980 and trastuzumab groups with statistical margins of 0.759 and 1.318. The population assessable for pathological complete response was defined as all randomised patients who received any amount of investigational product, underwent surgery, and had an available pathological complete response assessment from the local laboratory. The safety analysis population consisted of all patients who were randomised and received any amount of investigational product. We did sensitivity analyses in the intention-to-treat and per-protocol populations (data not shown). The intention-to-treat population included all patients randomly assigned to a study group, regardless of whether they received any investigational product. The per-protocol population included all patients who were randomised, had local laboratory pathological complete response results, and had no protocol deviations that prevented assessment of the primary objective. All statistical analyses were done with SAS version 9.1.3 or later.


Safety, efficacy, and clinical outcomes did not differ for the biosimilar ABP 980 and trastuzumab reference product in women with HER2-positive early breast cancer. The frequencies, types, and severities of adverse events, including cardiac events, did not differ between treatment groups and were consistent with the known safety profile of trastuzumab. Immunogenicity was low for both drugs. Similarities persisted in the neoadjuvant and adjuvant phases and switching from trastuzumab to ABP 980 did not lead to any new or unexpected safety signals. Overall, our results add to the evidence from analytical, functional, and pharmacokinetic studies supporting the clinical similarity of ABP 980 and trastuzumab.

157


Financement de l’étude Amgen. The funder had a role in study design, data analysis, data interpretation, and writing of the report, and had access to the raw data, but had no role in data collection. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.


GvM is a consultant for Amgen. MC is a consultant for AstraZeneca, Celldex, Novartis, OBI Pharma, Pfizer, Pierre Fabre, and Puma Biotechnology. H-CK is a consultant for Amgen, Carl Zeiss Meditec, Genomic Health, GSK, Janssen, LIV Pharma, Novartis, Pfizer, Roche, SurgVision, TEVA, and Theraclion. NZ and VH are employees and stockholders of Amgen. The other authors declare no competing interests.

Approbation éthique The protocol was reviewed and approved by the relevant independent ethics committees for each centre. All patients provided written informed consent. This study was done in accordance with the terms of the Declaration of Helsinki, Good Clinical Practice guidelines, and all applicable regulatory requirements.


Tableau D72 – Caractéristiques de Weinblatt 2018

Auteur, année Weinblatt et ses collaborateurs, 2018

Essai clinique


Phase 3


N.D.

Titre Switching from reference adalimumab to SB5 (adalimumab biosimilar) in patients with rheumatoid arthritis: Fifty-two-week phase III randomized study results

Objectif The 24-week equivalent efficacy and comparable safety results of the biosimilar SB5 and reference adalimumab (ADA) from the phase III randomized study in patients with moderate-to-severe rheumatoid arthritis (RA) have been reported previously. We undertook this transition study to evaluate patients who switched from ADA to SB5 or who continued to receive SB5 or ADA up to 52 weeks.

Devis et méthode ECRA double-blind, parallel-group study


N=544 BS n= 271, BS/BS n= 254 BR n= 254, BR/BS n= 125 ou BR/BR = 129

Critères inclusion

The study included patients ages 18–75 years with moderate-to-severe RA treated with methotrexate (MTX) for ≥6 months and receiving a stable MTX dosage of 10–25 mg/week for ≥4 weeks before screening. Patients had active disease (≥6 swollen joints, ≥ 6 tender joints, and either an erythrocyte sedimentation rate [ESR] ≥28 mm/hour or a serum C-reactive protein [CRP] level ≥1.0 mg/dl).

Critères exclusion

Pertinent exclusions included previous treatment with biologic agents and active or latent tuberculosis infection at screening

158



Intervention BR/BS Adalimumab/SB5, 40 mg subcutaneously every other week

Comparateur BR/BR Adalimumab 40 mg subcutaneously every other week




Milieu de dispensation des soins was conducted at 51 sites in 7 countries.

Durée du suivi 52 weeks; May 2014 to April 2015


Puissance The equivalence margin in the current study was determined on the basis of findings in previous studies of ADA 13, 14 and regulatory guidelines 15, 16. A meta‐analysis of 2 previous studies 13, 14 estimated a risk difference of 0.424 (95% confidence interval [95% CI] 0.239, 0.609) with a random‐effects model, and a risk difference of 0.383 (95%

CI 0.306, 0.461) with a fixed‐effects model, using the Mantel‐Haenszel weight. To preserve 50% of the effect of ADA over placebo, one‐half of the lower limit of the 95% CI for the treatment difference between ADA and placebo was calculated to be 0.12 (0.5 × 0.239) from a random‐effects model, and 0.15 (0.5 × 0.306) from a fixed‐effects model. A sample size of ≥245 patients per treatment group was required to achieve a significance level of 5% and a power of 80% for the primary analysis. Sample size was determined based on an equivalence margin of ±15%, an expected response rate of 63%, and a 12% dropout rate. The primary end point was analyzed for the difference between treatment groups, with 95% CIs, using the nonparametric covariance method, with geographic region used as stratification factor and baseline CRP level used as a covariate.

Type N.D.

Test Efficacy assessments were performed on the full analysis set, which comprised all randomized patients (intent-to-treat principle). The following treatment groups were compared: patients who were randomized to receive SB5 at week 0 (SB5 group), patients who were randomized to receive ADA at week 0 (ADA overall group), and to continue ADA (ADA/ADA group) or to switch to SB5 (ADA/SB5 group). Results are presented with no imputation for missing data. The safety population included all patients who received ≥1 dose of study drug after rerandomization at week 24. Safety results were compared for the SB5/SB5 group (patients in the SB5 group who were rerandomized to continue SB5), ADA/SB5 group, and ADA/ADA group. All efficacy and safety results were summarized descriptively by treatment group. Statistical analyses

159


were performed using SAS software, version 9.2 or higher (SAS Institute). patients in the ADA group who were rerandomized at week 24


In conclusion, SB5 was well tolerated over 1 year in patients with RA, with efficacy, safety, and immunogenicity comparable to those of ADA. Switching from ADA to SB5 had no treatment-emergent issues such as increased AEs, increased immunogenicity, or loss of efficacy.

Financement de l’étude Samsung Bioepis funded the study and facilitated the study design, provided writing assistance for the manuscript, and reviewed and approved the manuscript prior to submission. The authors independently collected the data, interpreted the results, and had the final decision to submit the manuscript for publication. Samsung Bioepis also funded medical writing assistance provided by Beena John, PhD (C4 MedSolutions, Yardley, PA; a CHC Group company). Publication of this article was not contingent upon approval by Samsung Bioepis.


Dr. Weinblatt has received consulting fees and/or honoraria from AbbVie, Amgen, Novartis, Roche, GlaxoSmithKline, Merck, Samsung Bioepis, Crescendo Bioscience, and AstraZeneca (less than $10,000 each) and from Bristol-Myers Squibb, Eli Lilly and Company, Pfizer, and UCB (more than $10,000 each) and research support from Amgen, Bristol-Myers Squibb, Crescendo Bioscience, Sanofi, and UCB. Dr. Baranauskaite has received consulting fees (less than $10,000) and research support from Samsung Bioepis. Drs. Dokoupilova, Zielinska, Jaworski, Racewicz, Pileckyte, and Jedrychowicz-Rosiak have received research support from Samsung Bioepis. Drs. Baek and Ghil own stock or stock options in Samsung Bioepis.

Approbation éthique The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Conference on Harmonisation Guidelines for Good Clinical Practice. Each study center’s independent ethics committee or institutional review board reviewed and approved the protocol and study. All patients provided written informed consent before study entry.


Tableau D73 – Caractéristiques de Yamanaka 2020

Auteur, année Yamanaka et ses collaborateurs, 2020

Essai clinique Nom (no) EudraCT 2015-002,809-12

Phase Phase 3


S.O.

Titre A comparative study to assess the efficacy, safety, and immunogenicity of YLB113 and the etanercept reference product for the treatment of patients with rheumatoid arthritis

Objectif The purpose of this study is to compare the efficacy and safety at week 24 of YLB113 50 mg and the RP 50 mg given once weekly as a subcutaneous (SC) injection in conjunction with methotrexate in patients with moderate-to-severe RA, and to evaluate the long-term safety and immunogenicity of YLB113 administration compared with the RP.

Devis et méthode ECRA, double-blind, randomized, parallel- group, active-control, comparative study


Stage A, N = 528 Stage B, n = 489 BR/BR: n = 235 BS/BS : n = 236 BR/BS ou BS/BR: n = 18

Critères inclusion

Patients eligible for inclusion were aged 18–75 years at the time of informed consent and were diagnosed with RA according to the 2010 ACR/European League Against Rheumatism (EULAR) classification criteria. Patients were required to exhibit a level of disease activity despite methotrexate treatment. Patients included had been treated with methotrexate for C 3 months at an optimum dose (6 mg–25 mg/week, not exceeding the local approved dose) that remained stable for C 6 weeks prior to screening. Patients were eligible if they had discontinued treatment with disease-modifying antirheumatic drugs other than methotrexate and completed a washout period of C 2 weeks or C 5 half-lives prior to drug administration, whichever was longer. For inclusion, patients were required to have C 6 tender joints and C 6 swollen joints (based on the swollen joint count [SJC] using 66 joints and tender joint count [TJC] using 68 joints) and DAS28 score C 3.2.

160


Critères exclusion

Exclusion criteria were known hypersensitivity to etanercept, acute or chronic infections, active tuberculosis, and known latex allergies.


Intervention Switch from etanercept to YLB113

Comparateur etanercept


Principal The primary endpoint of Stage A was the percentage of patients achieving an American College of Rheumatology (ACR)20 response at week 24 of dosing. The primary endpoints for stages B and C were safety assessments, including AEs and injection-site assessment, and immunogenicity at weeks 36, 44, and 52 of dosing.

Secondaires Secondary endpoints included ACR20 response rate at weeks 4, 8, and 12, ACR50 and ACR70 response rates at weeks 4, 8, 12, and 24 of dosing, and improvement in the DAS28 response rate at weeks 4, 8, 12, and 24. The DAS28 score was calculated based on either erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). To assess the individual DAS28 score during the course of the study, the same DAS assessment parameters (based on either ESR or CRP) were used throughout the study. Additional endpoints included AEs and immunogenicity assessment at weeks 4, 8, 12, and 24 of dosing.

Milieu de dispensation des soins 101 study centers located in the European Union, Japan, and India



Puissance N.D.

Type N.D.

Test Statistical data analysis was performed using SAS Version 9.3 or higher (SAS Institute, Inc; Cary, NC; 2000). Summary statistics and statistical analyses were performed for subjects included in the relevant analysis population. All statistical tests were two-sided and evaluated at a 5% level of significance. Missing ACR20 data were imputed using either a single mutation technique or a combination of non responder imputation and multiple imputation methods. Missing safety data were not imputed. However, because this was an international study that included patients with RA from Japan, Europe, and India, the outcome analysis for the primary and the most important secondary endpoint,

161


ACR20 and DAS28, respectively, has been performed based on different statistical methodology, including imputation techniques requested by the Pharmaceuticals and Medical Devices Agency (PMDA) and European Medicines Agency (EMA). The results therefore include, in addition to the EMA-requested analysis of ACR20 and DAS28, the last observation carried forward, which is the PMDARheumatol accepted analysis of missing data. An equivalence margin of 15% was estimated by carrying out meta-analysis of relevant studies and this approach was accepted by the EMA. The DAS28 reductions were analyzed using the least square means.

Conclusion générale des auteurs The lower immunogenicity of YLB113 does not affect its classification as a biosimilar based on clinical equivalency and safety results. Overall, the biosimilarity of YLB113 to the RP was demonstrated based on safety, efficacy, and immunogenicity in patients with moderate-to-severe RA. This can be extrapolated to other therapeutic indications that have been approved for treatment with etanercept.

Financement de l’étude Funding for the phase 3 study was provided by Yoshindo Lupin Biologics Ltd., Tokyo, Japan. Funding support for the Rapid Service Fee was provided by Mylan Inc. All authors had full access to all the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

Déclaration des conflits d’intérêts Dhananjay Bakhle is an employee and shareholder of Lupin Pharmaceuticals Ltd. Hisashi Yamanaka received grants and personal fees from YL Biologics Limited, and grants from AbbVie and Eisai. He received additional grants from Bristol- Myers, Novartis, Boehringer, Astellas, Kaken, Nippon Shinyaku, Pfizer, UCB, Ayumi, Ono, Daiichi-Sankyo, Taisho-Toyama, Takeda, Tanabe- Mitsubishi, Chugai, Teijin Pharma, and Torii, along with personal fees from Bristol- Myers, Pfizer, and Teijin Pharma. Naoyuki Kamatani has nothing to disclose. Yoshiya Tanaka has received speaking fees and/or honoraria from Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol- Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, and Teijin, and has received research grants from Asahi Kasei, Mitsubishi- Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, and Ono. Toshihiko Hibino is an employee of YL Biologics Limited. Edit Drescher has nothing to disclose. Juan Sańchez-Bursoń has nothing to disclose. Manfred Rettenbacher is an employee of Lupin Pharmaceuticals Ltd. and was during the conduct of the study. Girish Bhatia has nothing to disclose. Snehal Gadve was an employee of Lupin Pharmaceuticals Ltd. at the time the study was conducted. Chirag Shah is an employee of Lupin Pharmaceuticals Ltd.

Approbation éthique The study was conducted in accordance with the protocol, the ethical principles derived from international guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines, and applicable laws and regulations. The study was also conducted in accordance with the Japanese GCP in Japan and in accordance with ICH-GCP and/or local regulatory GCP in the European Union and India. An informed consent form (ICF) approved by each study center’s institutional review board/independent ethics committee was signed by the subject or their legally authorized representative (according to the regulatory and legal requirements of the participating country). The ICF contained all relevant information to be conveyed to the prospective subject to assist him/her in making an informed decision about participating in the study. The full list of institutional review boards/independent ethics committees that approved this study can be found in the Supplementary Material.


Tableau D74 – Caractéristiques de Yazici 2018

Auteur, année Yazici et ses collaborateurs, 2018

Essai clinique

Nom (no) N.D.

Phase N.D.


N.D.

Titre Analysis of real-world treatment patterns in a matched rheumatology population that continued innovator infliximab therapy or switched to biosimilar infliximab

Objectif This study compared treatment patterns of Turkish patients with a diagnosis of rheumatoid arthritis (RA) who were treated with innovator Remicade® (infliximab [IFX]) and either continued IFX or switched to CT-P13.

Devis et méthode Retrospective cohort (December 1, 2010–June 1, 2016)

162



N= 697 BR/BR n= 605 BR/BS n= 92

Critères inclusion

Adult patients were selected if they had ≥1 diagnosis claim for RA (International Statistical Classification of Diseases, tenth revision, clinical modification [ICD-10-CM] codes M05.X, M06.X) and continuous medical/pharmacy health plan enrollment during the study period from December 1, 2010, to June 1, 2016. Patients were required to have an initial IFX claim verified by a period of ≥12 months without a previous claim for IFX. The initial IFX claim date was designated as the index date. At least one subsequent prescription claims for IFX or CT-P13 during the period of CT-P13 availability was also required; the initial switch from IFX to CT-P13 was required to have occurred within 16 weeks of a prior IFX claim.

Critères exclusion

Patients with a diagnosis claim for pregnancy or cancer during the study period were excluded.


Intervention Switch from Remicade® (infliximab [IFX]) to CT-P13.

Comparateur Remain on Remicade® (infliximab [IFX])


Principal Treatment persistence

Secondaires S.O.

Milieu de dispensation des soins using the Turkish Ministry of Health database, a nationwide medical information collection system

Durée du suivi N.D.


Puissance N.D.

Type N.D.

163


Test Numbers and percentages were provided for dichotomous and polychotomous variables. Mean, median, and SD values were provided for continuous variables. P-values for dichotomous variables were calculated using chi-square tests, and P-values for continuous variables were calculated using the independent-samples t-tests. Statistical analyses were conducted using the Statistical Analysis System (SAS) Version 9.3.


These findings provide relevant and novel information about real-world utilization of an infliximab biosimilar in Turkey. Although reasons for discontinuation and clinical status were not available in the dataset, the apparent differences in discontinuation and switching rates in patients after switching to CT-P13 in this study, which were consistent with other studies, are significant and warrant further post-marketing analysis to assess the extent to which clinical or nonclinical factors contribute to lower persistency with CT-P13.

Financement de l’étude This study was funded by Janssen Scientific Affairs, LLC.


AO and LX are paid employees of STATinMED Research, which is a paid consultant to Janssen Scientific Affairs, LLC. YY is an employee of New York University and was a paid consultant to Janssen Scientific Affairs, LLC, in connection with this study and the development of this manuscript. During the conduct of this study and the drafting of this manuscript, IS was an employee of Guven Hospital and was a paid consultant to Janssen Scientific Affairs, LLC. LAE, KG, and AT are employees of Janssen Scientific Affairs, LLC, and are stockholders in Johnson & Johnson. The authors report no other conflicts of interest in this work.

Approbation éthique Since the data used for this study were de-identified and only aggregate results were reported, the study was exempt from the review of an Institutional Review Board.


Tableau D75 – Caractéristiques de Ye 2019

Auteur, année Ye et ses collaborateurs, 2019

Essai clinique Nom (no) NCT02096861

Phase Phase 3


Protocol amendments are detailed in the appendix.

Titre Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn’s disease: An international, randomised, double-blind, phase 3 non-inferiority study

Objectif The aims of this study were to establish non-inferior efficacy of CT-P13 compared with infliximab in patients with active Crohn’s disease who were naive to biological therapy, at week 6 using the Crohn’s Disease Activity Index (CDAI),17 as well as to assess endoscopy findings, inflammation biomarkers, pharmacokinetics, safety, and immunogenicity up to week 54 after switching or continued treatment at week 30.

Devis et méthode ECRA, Randomised, multicentre, double-blind, phase 3 non-inferiority study


308 patients were screened, of whom 220 were randomly assigned to receive CT-P13 (n=111; 56 in the CT-P13–CT-P13 group and 55 in the CT-P13–infliximab group) or infliximab (n=109; 54 in the infliximab–infliximab group and 55 in the infliximab–CT-P13 group) at week 0.

Critères inclusion

1. Patient is a male or female aged 18 to 75 years old, inclusive. 2. Patient has Crohn's disease with a score on the CDAI between 220 and 450 points and of at least 12 weeks’ disease duration prior to randomisation. 3. Patient has been treated for active Crohn’s disease but has not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant; or who is intolerant to or has medical contraindications for such therapies. Patients receiving the following treatments are eligible: • 5-aminosalicylates or antibiotics (if the dose remained constant for at least 4 weeks prior to randomisation) • Corticosteroids (prednisone, prednisolone, or budesonide) at the equivalent of 30 mg per day of prednisone or less (stable dose for 2 weeks prior to randomisation) • Azathioprine (stable dose for 8 weeks prior to randomisation) • 6-mercaptopurine (6-MP) (stable dose for 8 weeks prior to randomisation) • Methotrexate (MTX) (stable dose for 6 weeks prior to randomisation) For patients receiving corticosteroids, the following tapering regimen was recommended: Patients receiving corticosteroids were to maintain a stable dose until week 6, after which a defined tapering schedule could be started if the patient’s

164


condition had improved. Patients who entered the study receiving corticosteroid doses of more than 20 mg per day prednisone equivalent had their treatment tapered at a maximum rate of 5 mg per week; the maximum rate for patients receiving 20 mg per day prednisone equivalent or less was 2·5 mg per week. Any increase of steroid dose needed to be discussed in advance. 4. Patient has adequate renal and hepatic function at screening as defined by the following clinical chemistry results: • Serum creatinine < 1·5 × upper limit of normal (ULN) or an estimated creatinine clearance level > 50 mL/min (by Cockcroft-Gault formula) • Serum alanine aminotransferase < 2·5 × ULN • Serum aspartate aminotransferase < 2·5 × ULN • Serum total bilirubin < 2 × ULN 5. Patient has the following haematology laboratory test results at screening: • Haemoglobin ≥8·5 g/dL • White blood cell count ≥3·5 × 103 cells/μL (Système International [SI] units: ≥3·5 × 109 cells/L) • Neutrophil count ≥1·5 × 103 cells/μL (SI units: ≥1·5 × 109 cells/L) • Platelet count ≥100 × 103 cells/μL (SI units: ≥100 × 109 cells/L) 6. Patient has the ability to comprehend the full nature and purpose of the study, including possible risks and side effects, to cooperate with the investigator, to understand verbal and/or written instructions, and to comply with the requirements of the entire study. 7. Patient (or legal guardian, if applicable) is informed of the full nature and purpose of the study, including possible risks and side effects, is given ample time and opportunity to read and understand this information, and has signed and dated the written informed consent before inclusion in the study. 8. For both male and female patients, the patient and his or her partner of childbearing potential agree to use two of the following medically acceptable methods of contraception during the course of the study and for 6 months following discontinuation of study drug (excluding women who are not of childbearing potential and men who have been sterilised): • Barrier contraceptives (male condom, female condom, or diaphragm with a spermicidal gel) • Hormonal contraceptives (implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings) • Intrauterine device Male and female patients and their partners who have been surgically sterilised for less than 6 months prior to the date of informed consent must agree to use two medically acceptable methods of contraception. Menopausal females must have experienced their last period more than 12 months prior to the date of informed consent to be classified as not of childbearing potential.

Critères exclusion

1. Patient who has previously received a biological agent for the treatment of Crohn’s disease and/or a TNFα inhibitor for the treatment of other disease. 2. Patient who has allergies to any of the excipients of infliximab, any other murine and/or human proteins, or patient with a hypersensitivity to immunoglobulin product. 3. Patient who has a current or past history of chronic infection with hepatitis B, hepatitis C, or infection with human immunodeficiency virus (HIV)-1 or -2 or who has a positive result to the screening test for those infections. 4. Patient who has an acute infection requiring oral antibiotics within 2 weeks before randomisation, other serious infection within 6 months before randomisation, or a history of recurrent herpes zoster or other chronic or recurrent infection within 6 weeks before randomisation. 5. Patient who has a history of tuberculosis (TB) or a current diagnosis of TB or other granulomatous infections or other severe or chronic infection (such as sepsis, abscess or opportunistic infection, or invasive fungal infection such as histoplasmosis) or a past diagnosis without sufficient documentation of complete resolution following treatment. 6. Patient who has had recent exposure to persons with active TB, or patient who has a positive result to the screening test for latent TB (defined as a positive result for interferon-γ release assay [IGRA] with a negative examination of chest x-ray). A patient with sufficient documentation of prophylaxis or complete resolution following TB treatment based on local guidelines can be enrolled. If the result of the IGRA is indeterminate at screening, one retest will be possible during the screening period. If the repeated IGRA result is again indeterminate, the patient must be excluded from the study. If the repeated IGRA result is negative, the patient may be included in the study. Patients who have a positive result to the IGRA at initial or repeated test with negative examination of chest x-ray during screening. During screening, a patient with a positive

165


result for IGRA and a negative examination of chest x-ray who has received at least the first 30 days of country-specific TB therapy and intends to complete the entire course of that therapy can be enrolled. 7. Patient who is taking any of the following concomitant medications or treatment: • Alkylating agents within 12 months prior to randomisation • Live or live-attenuated vaccine within 8 weeks of randomisation • Any planned live or live-attenuated vaccination at the time of randomisation and/or during the study period • Any biological agents for the treatment of Crohn’s disease • Abdominal surgery within 6 months prior to randomisation • More than three small-bowel resection procedures prior to randomisation • Subtotal and total colectomy prior to randomisation • Any planned abdominal surgery at the time of randomisation and/or during the study period • Use of enteral or parenteral nutrition within 2 weeks prior to screening 8. Patient who has a medical condition including one or more of the following: • Classified as obese (body mass index ≥30 kg/m2) • Diabetes mellitus unless on a stable dosing regimen for at least 4 weeks prior to randomisation • Uncontrolled hypertension (as defined by systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg) • Active entero-vesical, entero-retroperitoneal, entero-cutaneous, and entero-vaginal fistulae within 6 months prior to screening. Entero-enteral fistulae without clinical significant symptoms upon investigator’s opinion and anal fistulae without draining problems are allowed • History of short bowel syndrome • Stoma (e.g. ileostomy or colostomy) within 6 months prior to randomisation • History of any malignancy within the 5 years prior to randomisation except completely excised and cured squamous carcinoma of the uterine cervix in situ, cutaneous basal cell carcinoma, or cutaneous squamous cell carcinoma • History of lymphoma or lymphoproliferative disease or bone marrow hyperplasia • New York Heart Association class III or IV heart failure, severe uncontrolled cardiac disease (unstable angina, arrhythmias, clinically significant electrocardiogram [ECG] abnormalities), or myocardial infarction within the 6 months prior to randomisation • History of organ transplantation, including corneal graft/transplantation • Any uncontrolled, clinically significant respiratory disease (in the opinion of the investigator), including but not limited to chronic obstructive pulmonary disease, asthma, bronchiectasis, or pleural effusion • Previous diagnosis or symptoms suggestive of demyelinating disorders, including multiple sclerosis and Guillain Barré syndrome • Any conditions significantly affecting the nervous system (i.e., neuropathic conditions or nervous system damage) • Any other serious acute or chronic medical or psychiatric condition that may increase the risk associated with study participation or investigational product administration or that may interfere with the interpretation of study results 9. Patient who has a current or past history of drug or alcohol abuse. 10. Patient who has had treatment with any other investigational device or medical product within 4 weeks of randomisation or five half-lives, whichever is longer. 11. Female patient who is currently pregnant, breastfeeding, or planning to become pregnant or breastfeed within 6 months of the last dose of study drug. 12. Patient who, in the opinion of his or her general practitioner or the investigator, should not participate in the study.

166



Intervention CT-P13, Infliximab BR

Comparateur CT-P13, Infliximab BR


Principal The primary efficacy endpoint was CDAI-70 response at week 6.

Secondaires Secondary efficacy endpoints were CDAI-70 response at week 14, clinical remission at weeks 6 and 14, and SIBDQ scores at weeks 0, 6, and 14. Tertiary efficacy endpoints Were CDAI-100 response at weeks 6, 14, 30, and 54, steroid free remission, sustained steroid-free remission, faecal calprotectin levels, and the proportion of patients with mucosal healing. Safety endpoints were incidence, causality, and severity of adverse events, including serious adverse events. Safety was assessed throughout the study via monitoring of adverse events, adverse events of special interest (infections and infusion-related reactions), and clinical laboratory results.

Milieu de dispensation des soins 58 centres in 16 countries (Belgium, Brazil, Denmark, France, Germany, Hungary, Italy, Israel, Mexico, the Netherlands, Poland, Republic of Korea, Romania, Russia, Ukraine, USA)



Puissance In total, 214 randomly assigned patients (107 patients initiating each drug) were required to achieve at least 85% power for a non-inferiority margin of –20% with a one-sided α level of 0·025. In the sample size calculation, the therapeutic non-inferiority of CT-P13 to infliximab was based on a response rate of 64·5%, as defined by CDAI-70 at week 6.20 The non-inferiority margin was defined as –20% to preserve 50% effectiveness of infliximab.

Type CDAI-70 and CDAI-100 response rates at weeks 6, 14, and 30 were analysed in the intention-to-treat population and the per-protocol population using the exact binomial approach, calculating a point estimate and 95% CI for the difference in proportion between the two treatment groups (infliximab vs CT-P13). The intention-to-treat population included all patients who were enrolled and randomly assigned to receive a dose of study drug (regardless of whether any study drug dosing was completed). The per-protocol population included all randomly assigned patients, except for those with major protocol deviations (as defined in the statistical analysis plan). Patients with missing or incomplete data for assessment of CDAI-70 response at week 6 were considered non-responders. CDAI-70 and CDAI-100 response rates, mucosal healing at week 54, steroid-free remission, and sustained steroid-free remission were analysed using the χ² test to analyse the difference in proportion between the four treatment groups. CRP levels, calprotectin levels, change from baseline in SIBDQ score, and PRO-2 scores were analysed using a t test for two-group analysis (up to week 30) and analysis of variance for four-group analysis at week 54. All analyses were performed based on a significance level of 0·05.

Test

Conclusion générale des auteurs In conclusion, this phase 3 RCT showed the therapeutic non-inferiority of CT-P13 to infliximab in patients with active Crohn’s disease. The results show that CT-P13 was well tolerated, with a similar safety profile to infliximab, and no clinically meaningful differences in immunogenicity.

Financement de l’étude Celltrion, Pfizer.

Déclaration des conflits d’intérêts BDY reports personal fees and non-financial support from Celltrion during the conduct of the study and personal fees from Abbvie Korea, Cornerstones Health, Ferring Korea, IQVIA, Janssen Korea, Kangstem Biotech, Kuhnil Pharm, Robarts Clinical Trials, Shire Korea, and Takeda Korea outside the submitted work. AL reports consultancy and

167


lecture fees from Takeda and lecture fees from Abbvie, Celltrion, and Janssen outside the submitted work. MLS reports advisory board fees from Janssen, Mundipharma, and Pfizer and advisory board and speaker fees from Abbvie and Takeda outside the submitted work. R-BM reports personal fees from Amgen outside the submitted work; personal fees and non-financial support from Abbvie, Alfa Sigma, Alvogen, Dr Reddys, Egis Pharmaceutical, MSD, and Takeda outside the submitted work; and grants from Abbvie outside the submitted work. K-ML reports consultancy and lecture fees from Takeda and consultancy fees from Celltrion outside the submitted work. CSE reports consultancy and lecture fees from Celltrion outside the submitted work. SJL is an employee of, and has stock options for, Celltrion. SYL and HUK are employees of Celltrion. SS reports consulting (advisory board) fees from AbbVie, Biogen/Samsung, Boehringer Ingelheim, Celltrion, Merck, Pfizer, Sandoz, Shire, and UCB outside the submitted work. HF reports consultancy fees from Pfizer UK Limited during the conduct of the study and consultancy fees from Pfizer UK Limited outside the submitted work. RC is an employee of Pfizer. Y-HK reports personal fees from Celltrion during the conduct of the study and personal fees from Chong Kun Dang Pharm, Eisai Korea, Ferring Korea, Janssen Korea, Shire Korea, and Takeda Korea outside the submitted work. MP, OA, MO, AD, SF, OL, and JHC declare no competing interests.

Approbation éthique The study protocol was reviewed and approved by independent ethics committees for each centre.


Tableau D76 – Caractéristiques de Yoo 2017

Auteur, année Yoo et ses collaborateurs, 2017

Essai clinique

Nom (no) PLANETRA extension study, NCT01571219

Phase 3


N.D.

Titre Efficacy and safety of CT-P13 (biosimilar infliximab) in patients with rheumatoid arthritis: Comparison between switching from reference infliximab to CT-P13 and continuing CT-P13 in the PLANETRA extension study

Objectif To assess the efficacy and safety of switching from the infliximab reference product (RP; Remicade®) to its biosimilar CT-P13 (Remsima®, Inflectra®) or continuing CT-P13 in patients with rheumatoid arthritis (RA) for an additional six infusions.

Devis et méthode ENCAA (open-label extension study (suite d’un ECRA))


N= 606 BS n= 302, BS/BS n= 158 BR n= 304, BR/BS n= 144

Critères inclusion

PLANETRA recruited patients aged 18–75 years with active RA for ≥1 year according to the 1987 American College of Rheumatology (ACR) classification criteria. Eligible patients did not respond adequately to ≥3 months of treatment with methotrexate (MTX) and received a stable MTX dose (12.5–25 mg/week) for ≥4 weeks before screening. Patients who had completed the main 54-week PLANETRA study were offered the opportunity to enter the extension study

Critères exclusion

N.D.

168

Auteur, année Yoo et ses collaborateurs, 2017


Intervention BR/BS CT-P13 (Remsima®, Inflectra®)/ Remicade® 2 h intravenous infusion of 3 mg/kg of CT-P13 (CELLTRION INC, Incheon, Republic of Korea) every 8 weeks

Comparateur S.O.




Milieu de dispensation des soins 100 centres across 19 countries in Europe, Asia, Latin America and Middle East.

Durée du suivi 40 semaines; March 2012 to July 2013


Puissance N.D.

Type N.D.

Test All data were analysed descriptively in the maintenance and switch groups. The populations were predefined in the study protocol and statistical analysis plan for participants of the extension study. The efficacy population included all patients who received at least one dose of study treatment and had at least one efficacy measurement in the extension study. Conservatively, ACR response was analysed using non-responder imputation (NRI) for missing values and presented with 95% CIs of the response rate using an exact binomial approach from the efficacy population. No imputation of missing values was done for analysis of other efficacy endpoints. The safety population consisted of all patients who enrolled in the study, because they had all received study treatment in the preceding study. Data from the main study period were analysed in participants of the extension study only, not in all patients in the main study. Methods for sensitivity analyses of ACR response and statistical analyses of exploratory and post hoc endpoints are included in online supplementary appendix A.


This multinational, open-label extension study demonstrated that in patients with RA receiving MTX, switching from RP to CT-P13 was not associated with any detrimental effects on efficacy, immunogenicity or safety. Additionally, this study demonstrated that CT-P13 remained efficacious and well tolerated over a 2-year treatment period.

Financement de l’étude This study was funded by CELLTRION Inc. The sponsor participated in study design, in the collection, analysis and interpretation of study data and in reviewing drafts of the manuscript. The final decision to submit the manuscript was made by the authors.


DHY and WP: consultation for CELLTRION. AB reports personal fees from Abbvie and grants from Samsung Bioepis and Abbvie, outside the submitted work; HUK, SJL and SYK are full-time employees of CELLTRION.

Approbation éthique Study protocols, consent forms and other written information were approved by the relevant MoH, each site’s institutional review board and independent EC for each study centre.


169

ANNEXE E

Tableaux de résultats

E.1. Gastroentérologie

E.1.1 Perte d’efficacité

Tableau E1 – Perte d’efficacité – Maladie de Crohn

Auteur, (année),

pays (Période à

l’étude)

Type d’étude (Nombre de

sites)

Critères d’inclusion et d’exclusion – Nombre et

caractéristiques des participants

Nombre total de

participants (n)

Caractéristiques des interventions

Paramètres de résultats

Résultats

Groupe contrôle (BR/BR)

Changement de traitement

(BR/BS)

Effet (IC à 95 %) Valeur de p

INFLIXIMAB

Guerra Veloz (2018 WJG) Espagne (Cohorte prospective : Mars 2015 à février 2016; cohorte rétrospective : janvier 2014 à mars 2015)

Cohorte prospective et rétrospective (1 site)

Inclusion : Cohorte rétrospective (BR/BR) : Atteints de MC ou de CU traités par infliximab BR ≥ 1 fois. Cohorte prospective (BR/BS) : Atteints de MC ou de CU ayant changé de l’infliximab BR à l'infliximab BS (CT-P13) Exclusion : N.D. Pour MC et UC Âge médian ± ET: BR/BR: 39,9 ± 12,5 ans BR/BS: 41 ± 12,7 ans Sexe, Femme (% total): BR/BR : 44,6 % BR/BS : 43,9 %

n = 196 BR/BR : n = 98 (MC : 67; CU : 31) BR/BS : n = 98 (MC : 67; CU : 31)

Cohorte rétrospective (BR/BR) : Sujets traités par infliximab BR Cohorte prospective (BR/BS) : Sujets ayant changé de l’infliximab BR à l'infliximab BS (CT-P13) Outil d’évaluation : MC : HBI CU : score Mayo partiel Rémission clinique : MC : HBI score ≤ 4 CU : score Mayo partiel ≤ 2 Durée du suivi : 12 mois

n/total (% total) Rémission clinique Maintien de rémission clinique

45/65 (69,2 %)

42/51

(82,3 %)

42/62 (67,7 %)

37/53

(69,8 %)

p = 0,992

p = 0,205

Jorgensen (2017) Norvège (Octobre 2014 à juillet 2015)

ECRA Double-insu (25 sites)

Inclusion : - Sujet > 18 ans (non enceinte ou allaitante)

- Diagnostic clinique : o Polyarthrite

rhumatoïde o Spondylarthrite o Arthrite psoriasique o Colite ulcéreuse

n = 482 BR/BR MC: 78 CU: 47 BR/BS MC: 77 CU: 46

Les sujets ont été maintenus sur l'infliximab BR (BR/BR) ou ont subi un changement de traitement, et ont été traités avec du CT-P13 (BR/BS). Les doses et les intervalles de perfusion des sujets sont

n/total (% total) Rémission clinique Aggravation de la maladie

46/66 (69,7 %)

14/66 (21,2%)

41/63 (65,1 %)

23/63 (36,5 %)

DTa : 6,1 (–9,6 à 21,9)

p = N.D.

DRa : -14,3 (-29,3 à 0,7)

p = N.D.

170

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


o Maladie de Crohn o Psoriasis en plaques

- Traité stablement avec l’infliximab BR durant les 6 derniers mois

Exclusion : - Comorbidité majeure - Changement majeur dans la co-médication

- Sans contraception adéquate

Âge moyen ± ET : BR/BR : MC : 38,0 ± 13,4 ans CU : 45,8 ± 14,1 ans BR/BS : MC : 39,5 ± 14,2 ans CU : 44,4 ± 14,8 ans Sexe : Femme (% total) : BR/BR : MC : 33 (42 %) CU : 18 (38 %) BR/BS : MC : 30 (39 %) CU : 14 (30 %)

restés inchangés par rapport à ceux avant la randomisation et le changement de traitement. Outil d’évaluation: MC : HBI CU : score Mayo partiel Aggravation de la maladie : MC : HBI score ≥ 7, associé à une hausse ≥ 4 CU : Score Mayo partiel ≥ 5, associé à une hausse ≥ 4 Rémission clinique: MC : HBI score ≤ 4 CU : Score Mayo partiel ≤ 2 Durée du suivi : 52 semaines

Ye (2019) 16 pays (Août 2014 à février 2017)


Inclusion : - Adulte (18-75 ans) - Atteint de MC depuis ≥12 semaines

- CDAI entre 220 et 450 - Ne répondant pas aux thérapies avec les corticostéroïdes ou les immunosuppréssants.

Exclusion : - Prise antérieure d’agents biologiques pour la MC

- Allergie ou hypersensibilité

- Infection chronique présente ou passée HBV, HCV, VIH1/2.

Semaines 0 à 30 n = 220 BR/BR : n = 54 BR/BS : n = 55 BS/BS : n = 56 BS/BR : n = 55 Semaines 30 à 54

Une portion des sujets a été traitée avec l’infliximab BR pendant 30 semaines et ensuite ils ont soit été maintenus sur l'infliximab BR (BR/BR) ou traités avec du CT-P13 (BR/BS). L’autre portion des sujets a été traitée avec du CT-P13 pendant 30 semaines et ensuite soit maintenus sur le CT-P13 (BS/BS) ou traités avec de l’infliximab BR (BS/BR). L’infliximab BR et le CT-P13 ont été administrés par

n/total (% total) Rémission clinique Rémission sans usage de stéroïdes

29/54 (53,7 %)

23/54

(42,6 %)

33/55 (60,0 %)

22/55

(40,0 %)

*p = 0,564

*p = 0,847

171

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


- Prise d’antibiotiques deux semaines avant la randomisation

Age médian (écart): BR/BR : 31 (18-69) ans BR/BS : 35 (19-63) ans BS/BS : 39 (19-68) ans BS/BR : 31 (18-69) ans Sexe, Femme, % total BR/BR : 28 (51,9 %) BR/BS : 21 (38,2 %) BS/BS : 27 (48,2 %) BS/BR : 21 (38,2 %)

n = 180 BR/BR : n = 41 BR/BS : n = 47 BS/BS : n = 48 BS/BR : n = 44

intraveineuse à une concentration de 5 mg/kg. Outil d’évaluation : CDAI Rémission clinique : CDAI score < 150 Rémission soutenue sans stéroïdes : CDAI score < 150 aux semaines 30 et 54 sans corticostéroïdes < 3 mois avant la semaine 54. Durée du suivi : 54 semaines

Groupe contrôle (BS/BS)


(BS/BR)


n/total (% total) Rémission clinique Rémission sans usage de stéroïdes

35/56 (62,5 %)

28/56

(50,0 %)

32/55 (58,2 %)

21/55

(38,2 %)

*p = 0,700

*p = 0,253

BR : Biologique de référence; BS : Biosimilaire; CDAI : Cronh’s Disease Activity index; DRa : Différence de risque ajustée; DTa : Différence de taux ajustée; ECRA : Essai contrôlé à randomisation aléatoire; ET : Écart type; HBI: Harvey–Bradshaw index; HBV : Virus de l’hépatite B; HCV : Virus de l’hépatite C; IC : Intervalle de confiance; MC : maladie de Crohn; N.D. : Non disponible; VIH : Virus de l'immunodéficience humaine * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

172

Tableau E2 – Perte d’efficacité – Colite Ulcéreuse

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB



Inclusion : Cohorte rétrospective (BR/BR) : Atteints de MC ou de CU traités par infliximab BR ≥ 1 fois. Cohorte prospective (BR/BS) : Atteints de MC ou de CU ayant changé de l’infliximab BR à l'infliximab BS (CT-P13) Exclusion : N.D. Pour MC et UC Âge médian ± ET: BR/BR: 39,9 ± 12,5 ans BR/BS: 41 ± 12,7 ans Sexe, Femme (% total): BR/BR : 44,6 % BR/BS : 43,9 %


Cohorte rétrospective (BR/BR) : Sujets traités par infliximab BR Cohorte prospective (BR/BS) : Sujets ayant changé de l’infliximab BR à l'infliximab BS (CT-P13) Outil d’évaluation : MC : HBI CU : score Mayo partiel Rémission clinique : MC : HBI score ≤ 4 CU : score Mayo partiel ≤ 2 Durée du suivi : 12 mois

n/total (% total) Rémission clinique Maintien de rémission clinique

21/28 (75,0 %)

20/23

(87,0 %)

18/26 (69,2 %)

17/21

(81,0 %)

p = 0,866

p = 0,890





rhumatoïde o Spondylarthrite o Arthrite psoriasique o Colite ulcéreuse o Maladie de Crohn o Psoriasis en plaques



n = 482 BR/BR MC: 78 CU: 47 BR/BS MC: 77 CU: 46

Les sujets ont été maintenus sur l'infliximab BR (BR/BR) ou ont subi un changement de traitement, et ont été traités avec du CT-P13 (BR/BS). Les doses et les intervalles de perfusion des sujets sont restés inchangés par rapport à ceux avant la randomisation et le changement de traitement. Outil d’évaluation: MC : HBI CU : score Mayo partiel

n/total (% total) Rémission clinique Aggravation de la maladie

29/33 (87,9 %)

3/33 (9,1 %)

39/42 (92,9 %)

5/42 (11,9 %)

DTa : -5,0 (-18,6 à 8,6)

p = N.D.

DRa : -2,6 (-15,2 à 10,0)

p = N.D.

173

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)



Nombre total de

participants (n)



Résultats



(BR/BS)




Aggravation de la maladie : MC : HBI score ≥ 7, associé à une hausse ≥ 4 CU : Score Mayo partiel ≥ 5, associé à une hausse ≥ 4 Rémission clinique: MC : HBI score ≤ 4 CU : Score Mayo partiel ≤ 2 Durée du suivi : 52 semaines

BR: Biologique de référence; BS: Biosimilaire; CU: Colite ulcéreuse; DRa : Différence de risque ajustée; DTa : Différence de taux ajustée; ECRA : Essai contrôlé à randomisation aléatoire; ET : Écart-type; HBI: Harvey–Bradshaw index; IC : Intervalle de confiance; MC: Maladie de Crohn; N.D. : Non disponible

174

Tableau E3 – Perte d’efficacité – Maladie inflammatoire de l’intestin (MC, CU, MII non classée)

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats


Changement de

traitement (BR/BS)


INFLIXIMAB

Kang (2018) République de Corée (Septembre 2015 à décembre 2016)

Cohorte prospective (1 site)

Inclusion : - Moins de 18 ans lors du

diagnostic - MII pédiatrique - Traité à l’infliximab BR

depuis ≥ 6 mois Exclusion : - Diagnostic de MII non

classé Age moyen ± ET: BR/BR : 17,3 ± 3,4 ans BR/BS : 17,5 ± 4,0 ans Sexe, Homme (% total) : BR/BR : 25 (69,4 %) BR/BS : 24 (63,2 %)

n = 74 BR/BR : n = 36 (MC: 28; CU: 8) BR/BS : n = 38 (MC: 32; CU: 6)

Les sujets ont été maintenus sur l'infliximab BR (BR/BR) ou ont subi un changement de traitement, et ont été traités avec du CT-P13 (BR/BS). Outil d’évaluation : MC : PCDAI et HBI CU : PUCAI et SCCAI Rémission clinique : MC : HBI score ≤ 4 et PCDAI score < 10 CU : SCCAI score ≤ 2 et PUCAI score < 10 Rémission persistante: Rémission clinique soutenue 1 an, sans usage de corticostéroïdes ou augmentation de dose. Durée du suivi : 1 an

n/total (% total) Rémission clinique Rémission persistante

.

28/31 (90,3 %)

28/36

(77,8 %)

31/35 (88,6 %)

30/38

(78,9 %)

p = 1,000

p = 1,000

Ratnakumaran (2018) Royaume-Uni (Février 2016 à janvier 2017)


Inclusion : Sujets atteints de MC ou de CU traités par infliximab BR. Exclusion : N.D. Âge moyen ± ET: BR/BR: 38,4 ± 14,8 ans BR/BS: 42,7 ± 15,3 ans Sexe, Femme (% total) BR/BR: 12 (63,2 %) BR/BS: 87 (45,5%)

n = 210 BR/BR : n = 19 (MC: 15; CU: 4; MII non classée: 0) BR/BS : n = 191 (MC: 173; CU: 14; MII non classée: 4)

Les sujets ont été maintenus sur l'infliximab BR (BR/BR) ou ont subi un changement de traitement, et ont été traités avec du CT-P13 (BR/BS). Outil d’évaluation : MC : HBI et CRP CU : Score de mayo partiel et CRP Rémission : - Général : Sujet

asymptomatique avec un CRP < 5 mg/L, sans corticostéroïde.

n/total (% total) Rémission clinique Réponse au traitement sans atteinte de rémission

9/19 (47,4 %)

2/19

(10,5 %)

111/191 (58,1 %)

24/111

(12,6 %)

p = 0,370

p = 0,800

175

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats


Changement de

traitement (BR/BS)


- MC fistulisante : Fermeture complète des fistules drainantes.

Réponse au traitement : - Général : Réponse

symptomatique avec amélioration du CRP, du HBI ou du score Mayo partiel.

- MC fistulisante: Amélioration du drainage des fistules.

Durée du suivi : 1 an

Van Hoeve (2019) Belgique (Juillet 2017 à janvier 2018)

Cohorte prospective et rétrospective (1 sites)

Inclusion : - Population pédiatrique atteint de MII

- Sujet traité avec de l’infliximab BR (Remicade®) depuis au moins 4 mois

- Thérapie de maintenance avec infliximab

Exclusion : N.D. Âge médian (écart) à l’initiation du traitement avec l’infliximab BR : 12,6 (9,4-14,3) ans Sexe, Femme (% total) : BR/BS : 21 (50 %)

n = 42 (MC : 26 CU: 16)

Les sujets ont été suivis sur une période de 6 mois avant le changement de traitement (BR/BR). Les sujets ont ensuite été suivis pendant 6 mois après le changement de traitement de l’infliximab BR au CT-P13 (BR/BS) Outil d’évaluation: MC : PCDAI CU : PCUDAI Rémission clinique: MC : PCDAI score < 10 CU : PUCDAI < 10 Durée du suivi : 6 mois avant changement, 6 mois après changement

n/total (% total) Rémission clinique

32/42 (76,2 %)

35/42 (83,3 %)

p = 0,289

ADALIMUMAB

Lukas (2020) République Tchèque

Cohortes rétrospectives associées (1 site)

Inclusion : - Population atteint de MII - Sujets traités avec de l’adalimumab BR ayant subi un changement non médical vers BS

Exclusion : N.D.

n = 186 BR/BR: 93 BR/BS: 93

Les sujets ont subi un changement de traitement, et ont été traités avec du SB5 (BR/BS) et ont été associés avec une cohorte rétrospective traitée avec adalimumab BR (BR/BR) Durée du suivi :

Activité de la pathologie : MC : HBI médian [écart] CU : partial Mayo médian [écart]

2 [1; 4]

1 [1; 3]

2 [0; 5]

1 [0; 2]

p = 0,179

p = 0,670

176

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats


Changement de

traitement (BR/BS)


(Novembre 2018 à mai 2019)

Âge médian (écart) : BR/BR 40 (33-52) ans BR/BS 40 (32-49) ans Sexe, Femme (% total) : BR/BR : 46 (49,5 %) BR/BS : 50 (53,7 %)

10 semaines

BR: Biologique de référence; BS: Biosimilaire; CRP : C-reactive protein; CU: Colite ulcéreuse; ET : Écart-type; HBI: Harvey–Bradshaw index; IC : Intervalle de confiance; MC: Maladie de Crohn; MII : Maladie inflammatoire de l’intestin; PCDAI : Pediatric CD Activity index; pMayo : partial Mayo score; PUCAI : Pediatric UC Activity index; SCCAI : Simple clinical colitis activity index

177

E.1.2 Immunogénicité

Tableau E4 – Immunogénicité – Maladie de Crohn

Auteur, (année),

pays (Période à

l’étude)


sites)

Critères d’inclusion et d’exclusion – Nombre

et caractéristiques des participants

Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB










Semaines 0 à 30 n = 220 BR/BR : n = 54 BR/BS : n = 55 BS/BS : n = 56 BS/BR : n = 55 Semaines 30 à 54 n = 180 BR/BR : n = 41 BR/BS : n = 47 BS/BS : n = 48 BS/BR : n = 44

Une portion des sujets a été traitée avec l’infliximab BR pendant 30 semaines et ensuite ils ont soit été maintenus sur l'infliximab BR (BR/BR) ou traités avec du CT-P13 (BR/BS). L’autre portion des sujets a été traitée avec du CT-P13 pendant 30 semaines et ensuite soit maintenus sur le CT-P13 (BS/BS) ou traités avec de l’infliximab BR (BS/BR). L’infliximab BR et le CT-P13 ont été administrés par intraveineuse à une concentration de 5 mg/kg. Durée du suivi : 54 semaines

n/total (% total) AAM positif Nouveaux AAM positif Nouveau AAMN positif

21/54 (38,9 %)

0/54 (0 %)

0/54 (0 %)

30/55 (54,5 %)

7/55

(12,7 %)

0/55 (0 %)

*p = 0,126

*p = 0.012

p = S.O.



(BS/BR)


n/total (% total) AAM positif Nouveaux AAM positif Nouveau AAMN positif

22/56 (39,3 %)

2/56

(3,6 %)

1/56 (1,8 %)

18/55 (32,7 %)

3/55

(5,4 %)

1/55 (1,8 %)

*p = 0,554

*p = 0,679

*p = 1,000

AAM : Anticorps anti-médicament; AAMN, anticorps anti-médicament neutralisant; BR : Biologique de référence; BS : Biosimilaire; CDAI : Cronh’s Disease Activity index; ECRA : Essai contrôlé à randomisation aléatoire; HBV : Virus de l’hépatite B; HCV : Virus de l’hépatite C; IC : Intervalle de confiance; MC : Maladie de Crohn; N.D. : Non disponible; S.O. : Sans objet; VIH : Virus de l'immunodéficience humaine * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

178

Tableau E5 – Immunogénicité – Maladie inflammatoire de l’intestin (MC, CU, MII non classée)

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB



Inclusion : - Moins de 18 ans lors

du diagnostic - MII pédiatrique - Traité à l’infliximab

BR depuis ≥ 6 mois Exclusion : - Diagnostic de MII non



Les sujets ont été maintenus sur l'infliximab BR (BR/BR) ou ont subi un changement de traitement, et ont été traités avec du CT-P13 (BR/BS). Durée du suivi : 1 an

n/total (% total) AAM positif Nouveaux AAM positif

28/31 (90,3 %)

2/36

(5,6 %)

33/35 (94,3 %)

1/38

(2,6 %)

p = 0,888

*p = 0,610

ADALIMUMAB

Lukas (2020) République Tchèque (Novembre 2018 à mai 2019)

Cohortes rétrospectives associées (1 site)

Inclusion : - Population atteint de MII

- Sujets traités avec de l’adalimumab BR ayant subi un changement non médical vers BS

Exclusion : N.D. Âge médian (écart) : BR/BR 40 (33-52) ans BR/BS 40 (32-49) ans Sexe, Femme (% total) : BR/BR : 46 (49,5 %) BR/BS : 50 (53,7 %)

n = 186 BR/BR: 93 BR/BS: 93

Les sujets ont subi un changement de traitement, et ont été traités avec du SB5 (BR/BS) et ont été associés avec une cohorte rétrospective traitée avec adalimumab BR (BR/BR) Durée du suivi : 10 semaines

n/total (% total) AAM positif

2/93 (2,2 %)

2/93 (2,2 %)

*p = 1,000

AAM : Anticorps anti-médicament; BR: Biologique de référence; BS: Biosimilaire; CU: Colite ulcéreuse; ET : Écart-type; IC : Intervalle de confiance; MC: Maladie de Crohn; MII : Maladie inflammatoire de l’intestin * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

179

E.1.3 Effets indésirables Tableau E6 – Effets indésirables – Maladie de Crohn

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB


Cohortes prospective et rétrospective (1 site)

Inclusion : Cohorte rétrospective (BR/BR) : Sujets atteints de MC ou de CU traités par infliximab BR au moins une fois en 2014. Cohorte prospective (BR/BS) : Sujets atteints de MC ou de CU ayant changé de l’infliximab BR à l'infliximab BS (CT-P13) et ayant été suivis 12 mois. Exclusion : N.D. Pour MC et UC Âge médian ± ET: BR/BR: 39,9 ± 12,5 ans BR/BS: 41 ± 12,7 ans Sexe, Femme (% total): BR/BR : 44,6 % BR/BS : 43,9 %


Cohorte rétrospective (BR/BR) : Sujets traités par infliximab BR Cohorte prospective (BR/BS) : Sujets ayant changé de l’infliximab BR à l'infliximab BS (CT-P13) Durée du suivi : 12 mois

n/total (% total) EIAT causant l’arrêt du traitement

2/67 (3,0 %)

4/67 (6,0 %)

*p = 0,680







Semaines 0 à 30 n = 220 BR/BR : n = 54 BR/BS : n = 55 BS/BS : n = 56 BS/BR : n = 55

Une portion des sujets a été traitée avec l’infliximab BR pendant 30 semaines et ensuite ils ont soit été maintenus sur l'infliximab BR (BR/BR) ou traités avec du CT-P13 (BR/BS). L’autre portion des sujets a été traitée avec du CT-P13 pendant 30 semaines et ensuite soit maintenus sur le CT-P13 (BS/BS) ou traités avec de l’infliximab BR (BS/BR).

n/total (% total) EIAT EIGAT EIAT causant l’arrêt du traitement

14/54

(25,9 %)

0/54 (0 %)

3/54

(5,6 %)

21/55

(38,2 %)

2/55 (3,6 %)

3/55

(5,5 %)

*p = 0,194

*p = 0,495

*p = 1,000

n/total (% total) EIAT

18/56

15/55

*p = 0,679

180

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)



Nombre total de

participants (n)



Résultats



(BR/BS)





Semaines 30 à 54 n = 180 BR/BR : n = 41 BR/BS : n = 47 BS/BS : n = 48 BS/BR : n = 44

L’infliximab BR et le CT-P13 ont été administrés par intraveineuse à une concentration de 5 mg/kg. Durée du suivi : 54 semaines

EIGAT EIAT causant l’arrêt du traitement

(32,1 %)

1/56 (1,8 %)

3/56

(5,4 %)

(27,2 %)

1/55 (1,8 %)

3/55

(5,5 %)

*p = 1,000

*p = 1,000

BR : Biologique de référence; BS : Biosimilaire; CDAI : Cronh’s Disease Activity index; CU: Colite ulcéreuse; ECRA : Essai contrôlé à randomisation aléatoire; EIAT : Effets indésirables apparus en cours de traitement; EIGAT: Effets indésirables graves apparus en cours de traitement; ET : Écart-type; HBV : Virus de l’hépatite B; HCV : Virus de l’hépatite C; IC : Intervalle de confiance; MC : Maladie de Crohn; VIH : Virus de l'immunodéficience humaine * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

181

Tableau E7 – Effets indésirables – Colite ulcéreuse

Auteur, (année),

pays (Période à

l’étude)


sites)

Critères d’inclusion et d’exclusion – Nombre et caractéristiques des

participants

Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB






n/total (% total) EIAT causant l’arrêt du traitement

1/31 (3,2 %)

2/31 (6,5 %)

*p = 1,000

BR: Biologique de référence; BS: Biosimilaire; CU: Colite ulcéreuse; EIAT : Effets indésirables apparus en cours de traitement; ET : Écart-type; IC : Intervalle de confiance; MC: Maladie de Crohn * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

182

Tableau E8 – Effets indésirables – Maladie inflammatoire de l’intestin (MC, CU, MII non classée)

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)


participants

Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB






n/total (% total) EI EIG EI causant l’arrêt du traitement Effets indésirables graves

- Réactivation du VHB - Carcinome cervical - Syndrome de Sweet

9/98 (9,2 %)

2/98

(2,0 %)

4/98 (4,1 %)

11/98 (11,2 %)

2/98

(2,0 %)

6/98 (6,1 %)

p = 0,814

*p = 1,000

*p = 0,539




du diagnostic - MII pédiatrique - Traité à l’infliximab BR

depuis ≥ 6 mois Exclusion : - Diagnostic de MII non

classé Age moyen ± ET: BR/BR : 17,3 ± 3,4 ans BR/BS : 17,5 ± 4,0 ans Sexe, Homme (% total): BR/BR : 25 (69,4 %) BR/BS : 24 (63,2 %)



n/total (% total) EI EIG EI causant l’arrêt du traitement

22/36 (61,1 %)

0/36 (0 %)

0/36 (0 %)

23/38 (60,5 %)

0/38 (0 %)

0/38 (0 %)

*p = 1,000

S.O.

S.O.

183

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)


participants

Nombre total de

participants (n)



Résultats



(BR/BS)


Ratnakumaran (2018) Royaume-Uni (Février 2016 à janvier 2017)


Inclusion : Sujets atteints de MC ou de CU traités par infliximab BR. Exclusion : N.D. Âge moyen ± ET: BR/BR: 38,4 ± 14,8 ans BR/BS: 42,7 ± 15,3 ans Sexe, Femme (% total) BR/BR: 12 (63,2 %) BR/BS: 87 (45,5%)

n = 210 BR/BR : n = 19 (MC: 15; CU: 4; MII non classée: 0) BR/BS : n = 191 (MC: 173; CU: 14; MII non classée: 4)


n/total (% total) EI causant l’arrêt du traitement

0/19 (0 %)

9/191 (4,7 %)

*p = 1,000

Van Hoeve (2019) Belgique (Juillet 2017 à janvier 2018)

Cohorte prospective et rétrospective (1 sites)

Inclusion : - Population pédiatrique atteint de MII

- Sujet traité avec de l’infliximab BR (Remicade®) depuis au moins 4 mois

- Thérapie de maintenance avec infliximab

Exclusion : N.D. Âge médian (écart) à l’initiation du traitement avec l’infliximab BR : 12,6 (9,4-14,3) ans Sexe, Femme (% total) : BR/BS : 21 (50 %)

n = 42 (MC : 26 CU: 16)

Les sujets ont été suivis sur une période de 6 mois avant le changement de traitement (BR/BR). Les sujets ont ensuite été suivis pendant 6 mois après le changement de traitement de l’infliximab BR au CT-P13 (BR/BS) Durée du suivi : 6 mois avant changement, 6 mois après changement

n/total (% total) EI EIG EI causant l’arrêt du traitement Effets indésirables graves :

- Résection iléo-caecale

26/42 (61,9 %)

1/42 (0 %)

0/42 (0 %)

18/42 (42,9 %)

1/42

(2,4 %)

1/42 (2,4 %)

p = 0,317

*p = 1,000

*p = 1,000

BR: Biologique de référence; BS: Biosimilaire; CU: Colite ulcéreuse; EI : Effets indésirables; EIG : Effets indésirables graves; ET : Écart-type; IC : Intervalle de confiance; MC: Maladie de Crohn; MII : Maladie inflammatoire de l’intestin; S.O. : Sans objet * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

184

E.1.4 Rétention

Tableau E9 – Rétention – Maladie de Crohn

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)


participants

Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB






n/total (% total) Rétention Raisons (n/total arrêté) : - EI - Perdu au suivi

65/67 (97,0 %)

2/2 0/2

62/67 (92,5 %)

4/5 1/5

*p = 0,441

S.O. S.O.






Semaines 0 à 30 n = 220 BR/BR : n = 54 BR/BS : n = 55 BS/BS : n = 56 BS/BR :

Une portion des sujets a été traitée avec l’infliximab BR pendant 30 semaines et ensuite ils ont soit été maintenus sur l'infliximab BR (BR/BR) ou traités avec du CT-P13 (BR/BS). L’autre portion des sujets a été traitée avec du CT-P13 pendant 30 semaines et ensuite soit maintenus sur le CT-P13 (BS/BS) ou traités avec de l’infliximab BR (BS/BR).

n/total (% total) Rétention

37/41 (90,2 %)

45/47 (95,7 %)

*p = 0,411



(BS/BR)



44/48 (91,7 %)

40/44 (90,9 %)

*p = 1,000

185

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)


participants

Nombre total de

participants (n)



Résultats



(BR/BS)






n = 55 Semaines 30 à 54 n = 180 BR/BR : n = 41 BR/BS : n = 47 BS/BS : n = 48 BS/BR : n = 44

L’infliximab BR et le CT-P13 ont été administrés par intraveineuse à une concentration de 5 mg/kg. Durée du suivi : 54 semaines

BR : Biologique de référence; BS : Biosimilaire; CDAI : Cronh’s Disease Activity index; CU: Colite ulcéreuse; ECRA : Essai contrôlé à randomisation aléatoire; ET : Écart-type; HBV : Virus de l’hépatite B; HCV : Virus de l’hépatite C; IC : Intervalle de confiance; MC : Maladie de Crohn; S.O. : Sans objet; VIH : Virus de l'immunodéficience humaine * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

186

Tableau E10 – Rétention – Colite ulcéreuse

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB






n/total (% total) Rétention Raisons (n/total arrêté) : - EI - Rémission

28/31

(90,3 %)

1/3 2/3

26/31

(83,9 %)

2/5 3/5

*p = 0,707

S.O. S.O.

BR: Biologique de référence; BS: Biosimilaire; CU: Colite ulcéreuse; ET : Écart-type; IC : Intervalle de confiance; MC: Maladie de Crohn; S.O. : Sans objet * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

187

Tableau E11 – Rétention – Maladie inflammatoire de l’intestin (MC, CU)

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB




du diagnostic - MII pédiatrique - Traité à l’infliximab

BR depuis ≥ 6 mois Exclusion : - Diagnostic de MII non


n = 74 BR/BR: n = 36 (MC: 28; CU: 8) BR/BS: n = 38 (MC: 32; CU: 6)


n/total (% total) Rétention Raisons (n/total arrêté) : - Manque d’efficacité - Rémission - Perdu au suivi

31/36 (86,1 %)

2/5 2/5 1/5

35/38 (92,1 %)

1/3 1/3 1/3

p = 0,649

S.O. S.O. S.O.

BR: Biologique de référence; BS: Biosimilaire; CU: Colite ulcéreuse; ET : Écart-type; MC: Maladie de Crohn; MII : Maladie inflammatoire de l’intestin; S.O. : Sans objet

188

E.2. Rhumatologie


Tableau E12 – Perte d’efficacité – Polyarthrite rhumatoïde

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats

Évaluation de control (BR/BR)


(BR/BS)


INFLIXIMAB

Alten (2019) 28 pays (Août 2014 à juin 2017)

ECRA Double insu Groupes parallèles (184 sites)

Inclusion : - Adultes (≥ 18 ans) - Diagnostic de PR depuis ≥ 4 mois

- PR active, modérée à sévère

- Dose stable de MTX (10–25 mg/sem) depuis ≥4 semaines

Exclusion : Traités précédemment avec infliximab ou des thérapies appauvrissant les lymphocytes. Âge moyen ± ET BR/BR 52,8 ± 12,9 ans BR/BS 52,8 ± 13,3 ans Sexe Femme (% total): BR/BR : 264 (81,0 %) BR/BS : 258 (79,6 %)

Phase 2 n = 566 BR/BR n = 143 BR/BS n = 143 BS/BS n = 280

Phase 2 (semaine 30) : Les sujets ont été maintenus sur l'infliximab BR (Remicade®) (BR/BR) ou ont subi un changement de traitement et ont été traités avec le BS PF-SZ-IFX (BR/BS). Injections intraveineuses de 3 mg/kg à chaque 8 semaines. Dose stable de MTX (10–25 mg/sem) et acide folique pour la durée de l’étude. Durée du suivi : 24 semaines

ACR20, n/total (% réponse) ACR50, n/total (% réponse) ACR70, n/total (% réponse) DAS28-CRP, moyenne

92/143

(64,3 %)

61/143 (42,7 %)

33/143

(23,1 %)

3,6

101/143 (70,6 %)

65/143

(45,5 %)

35/143 (24,5 %)

3,6

*p = 0,313

*p = 0,721

*p = 0,890

S.O. .

Smolen (2018) 11 pays (Août 2013 à août 2015)

ECRA Double-insu Groupes parallèles (73 sites)

Inclusion : - Adultes (18 à 75 ans) - Diagnostic de PR depuis ≥ 6 mois


- Prise de MTX depuis ≥ 6 mois et des doses stables depuis ≥ 4 semaines

- Devait avoir complété les 54 premières semaines.

Exclusion :

Semaines 0 à 54 n = 584 BR n = 293 BS n = 291, Semaines 54 à 78 BS/BS n = 201 BR/BR n = 101 BR/BS n = 94

Semaine 54 : Les sujets ont été maintenus sur l'infliximab (Remicade®) BR (BR/BR) ou ont subi un changement de traitement et ont été traités avec le biosimilaire SB2 (BR/BS). Perfusion intraveineuse de BR ou BS de 2 h à 3 mg/kg chaque 8 semaines. MTX

ACR20, n/total (% réponse) ACR50, n/total (% réponse) ACR70, n/total (% réponse) EULAR, n/total (% réponse)

• Bonne réponse

64/93

(68,8 %)

44/93 (47,3 %)

29/93

(31,2 %)

32/93 (34,4 %)

54/85

(63,5 %)

32/85 (37,6 %)

19/85

(22,4 %)

28/85 (32,9 %)

*p = 0,526

*p = 0,226

*p = 0,237

*p = 0,875

189

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


Troubles médicaux importants au cours des 54 premières semaines Âge moyen ± ET BR/BR 51,5 ± 11,2 ans BR/BS 53,0 ± 11,0 ans Sexe Femme (% total): BR/BR : 79 (78,2 %) BR/BS :77 (81,9 %)

(10–25 mg/sem) et acide folique (5–10 mg/sem) Durée du suivi : 24 semaines

• Réponse modérée

47/93

(50,5 %)

44/85

(51,8 %)

*p = 0,882

Glintborg (2017) Danemark (Janvier 2016 à 2018)

Cohorte rétrospective et historique (3 sites)

Inclusion : Sujets atteints d’arthrite inflammatoire présent dans le registre DANBIO, plus 2 hôpitaux, qui ont changé de infliximab BR pour le BS CT-P13. Exclusion : N.D. Pour PR Âge médian (écart) BR/BS : 63 (51-71) ans Sexe Femme (% total): BR/BS : 281 (70 %)

n = 802 PR n = 403 BR/BS n = 403 Sous-groupe avec données pour ΔPreswitch = 276 ΔPostswitch = 265

Changement de traitement de l'infliximab BR au BS (CT-P13) selon la posologie recommandée (BR/BS). Durée du suivi : médiane (écart) : 413 (339–442) jours ΔPreswitch = 3 mois ΔPostwitch = 3 mois

Changement médian de DAS28 dans le temps (écart)

ΔPreswitch

0,1 (−0,2 à 0,5)

ΔPostswitch

0,0 (−0,4 à 0,4)

p = 0,8

ADALIMUMAB

Cohen (2018) 14 pays (Janvier 2015 à mars 2016)


Inclusion : - Adultes (18 à 80 ans) - PR active, modérée à sévère depuis ≥ 6 mois

- Dose stable de MTX (15-25 mg/sem) depuis ≥ 12 semaines

Exclusion : - Traités précédemment avec adalimumab ou > 1 autres médicaments biologiques

- Infection active - Hypersensibilité ou EI à des agents similaires aux médicaments à l'étude ou à leurs excipients

Semaines 0 à 24 n = 645 BR n = 321 BS n = 324 Semaines 24 à 48 n = 593 BR/BR n = 148 BR/BS n = 147 BS/BS n = 298

Semaine 24 : Les sujets ont été maintenus sur l’adalimumab (Humira®) BR (BR/BR) ou ont subi un changement de traitement et ont été traités avec le BS BI 695501 (BR/BS). Humira® ou BI 695501 : 40 mg sous cutané par seringue préremplies une fois toutes les 2 semaines. Dose stable de MTX (15-25 mg/sem)

EULAR, n/total (% réponse)

• Bonne réponse

• Réponse modérée

52/148 (35 %)

69/148 (47 %)

46/147 (31 %)

76/147 (52 %)

*p = 0,537

*p = 0,416

190

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


Âge moyen ± ET BR/BR 53,6 ± 11,3 ans BR/BS 53,7 ± 12,0 ans Sexe Femme (% total): BR/BR : 269 (83,8 %) BR/BS : 267 (82,4 %)

Durée du suivi : 24 semaines

Weinblatt (2018) 7 pays (Mai 2014 à avril 2015)



- Dose stable de MTX (10-25 mg/sem) depuis ≥4 semaines

Exclusion : - Traitement préalable avec un médicament biologique

- Tuberculose active ou latente


Semaines 0 à 24 n = 544 BR n = 254, BS n = 271 Semaine 24 à 52 BR/BR = 129 BR/BS n = 125 BS/BS n = 254

Semaine 24 : Les sujets ont été maintenus sur l’adalimumab (Humira®) BR (BR/BR) ou ont subi un changement de traitement et ont été traités avec le BS SB5 (BR/BS). Humira® ou SB5 : 40 mg sous cutané toutes les 2 semaines Durée du suivi : 28 semaines

ACR20, n/total (% réponse) ACR50, n/total (% réponse) ACR70, n/total (% réponse) Changement moyen de DAS28 dans le temps

91/124

(73,4 %)

63/124 (50,8 %)

35/124

(28,2 %)

-2,92

93/118

(78,8 %)

64/118 (54,2 %)

31/118

(26,3 %)

-3,02

*p = 0,367

*p = 0.609

*p = 0,774

p = N.D.

ETANERCEPT

Glintborg (2019) Danemark (Avril 2016 à janvier 2017; cohorte historique : janvier 2014)


Inclusion : Tous les sujets atteints PR, SA ou AP traités avec ETA BR. Exclusion : N.D. Pour PR Âge moyen (écart) BR/BR 62 (48-70) ans BR/BS 61 (49-70) ans Sexe Femme (% total): BR/BR : 217 (76 %) BR/BS : 689 (74 %)

PR n = 1219 BR/BS n = 933 Sous-groupe BR/BS avec données pour ΔPreswitch = 485 ΔPostwitch = 436

Changement de traitement de l'ETA BR au BS (SB4) selon la posologie recommandée (BR/BS). Durée du suivi : Médian (écart) BR/BS : 383 (314–414) jours ΔPreswitch = 3 mois ΔPostwitch = 3 mois


ΔPreswitch

0,0 (0,0 à 0,0)

ΔPostswitch

0,0 (−0,4 à 0,5)

p = N.D.

191

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


RITUXIMAB

Shim (2019) Europe, Asie du Pacifique, Amérique Latine (Août 2014 à janvier 2017)


Inclusion : - Adultes (18 à 75 ans) - PR active - Dose stable de MTX (7,5-25 mg/sem) depuis ≥ 12 semaines

- Réponse inadéquate ou intolérance à la thérapie anti-TNF par infliximab

Exclusion : - Prise de plus de 2 agents biologiques.

- Prise antérieure de rituximab ou participation à une étude de BS sur le rituximab.

Âge moyen ± ET BR1/BR1: 51,9 ± 10,3 ans BR1/BS : 52,3 ± 11,2 ans BR2/BS : 50,1 ± 10,7 ans Sexe Femme (% total): BR1/BR1 : 54 (84,4 %) BR1/BS : 55 (88,7 %) BR2/BS : 40 (85,1 %)

Semaines 0 à 48 n = 372 BR1 = 151 BR2 = 60 BS = 161 Semaines 48 à 72 BR1/BR1 = 64 BR1/BS = 62 BR2/BS = 47 BS/BS = 120 BR1: EU-Rituximab BR2: UE-Rituximab BS: CT-P10

Semaine 48 Les sujets ont été maintenus sur le BR1 (BR/BR) ou ont changé de traitement vers BS (BR1/BS). Les sujets sur BR2 ont tous changé de traitement au BS (BR2/BS) Chaque cycle comprenait deux perfusions intraveineuses de 1 g de CT-P10 ou Rituximab séparées par un intervalle de 2 semaines Durée du suivi : 24 semaines

ACR20, n/total (% réponse) ACR50 n/total (% réponse) ACR70 n/total (% réponse) DAS28-CRP, moyenne(±ET) DAS28-ESR, moyenne(±ET) ACR20, n/total (% réponse) ACR50 n/total (% réponse) ACR70 n/total (% réponse) DAS28-CRP, moyenne(±ET) DAS28-ESR, moyenne(±ET)

53/64 (82,8 %)

40/64

(62,5 %)

27/64 (42,2 %)

2,8 (1,4)

3,4 (1,5)

53/64 (82,8 %)

40/64

(62,5 %)

27/64 (42,2 %)

2,8 (1,4)

3,4 (1,5)

BR1/BS

50/60 (83,3 %)

40/60

(66,7 %)

29/60 (48,3 %)

2,8 (1,2)

3,4 (1,3)

BR2/BS

45/47 (95,7 %)

28/47

(59,6 %)

19/47 (40,4 %)

3,0 (1,2)

3,6 (1,2)

*p = 1,000

*p = 0,708

*p = 0,588

S.O.

S.O.

*p = 0,041

*p = 0,844

*p = 1,000

S.O.

S.O.

ACR20-50-70 : Amélioration du nombre d'articulations douloureuses et du nombre de synovites (≥20 % - 50% - 70 %); AP : Arthrite psoriasique; BR : Biologique de référence; BS : Biosimilaire; DANBIO : Régistre nationale Danois; DAS28 : Score d’activité de la maladie en 28 points (Disease Activity Score); CRP : Protéine C-réactive; ESR : Vitesse de sédimentation des érythrocytes; ECRA : Essai comparatif à randomisation aléatoire; EI : Effets indésirables; ECRNA : Étude essais clinique à répartition non aléatoire; ET : Écart-type; ETA : Etanercept; EULAR : European League Against Rheumatism; MTX : Méthotrexate; PR : Polyarthrite rhumatoïde; SA : Spondylarthrite ankylosante; UE : Union européenne; EU : États-Unis * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

192

Tableau E13 – Perte d’efficacité – Spondylarthrite ankylosante

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de participants (n)



Résultats



(BR/BS)


INFLIXIMAB



Inclusion : Sujets atteints d’arthrite inflammatoire présent dans le registre DANBIO, plus 2 hôpitaux, qui ont changé de infliximab BR pour le BS CT-P13. Exclusion : N.D. Pour SA Âge médian (écart) BR/BS 47 (39-55) ans Sexe Femme (% total): BR/BS : 73 (26 %)

n = 802 SA n = 279 BR/BS n = 279 Sous-groupe avec données pour ΔPreswitch = 160 ΔPostswitch = 169


Changement médian de BASDAI dans le temps (écart) Changement médian de ASDAS dans le temps (écart)

ΔPreswitch

0,0 (-4,0 à 5,0)

0,0 (−0,3 à 0,4)

ΔPostswitch

0,0 (-4,0 à 7,0)

0,0 (−0,3 à 0,3)

p = 0,3

p = 0,8

Kaltsonoudis (2019) Grèce (Janvier 2017 à décembre 2018)


Inclusion : - Diagnostic de SA - Traité avec Infliximab BR

- Aucun autre médicament biologique auparavant

- En rémission clinique. Exclusion : N.D. Age moyen ± ET BR/BR 35,7 ± 4,3 ans BR/BS 36,1 ± 4,6 ans Sexe Homme (% total): BR/BR : 40 (93 %) BR/BS : 39 (87 %)

n = 88 BR/BR n = 43 BR/BS n = 45

Changement de traitement de l'infliximab BR au BS CT-P13 selon la posologie recommandée (5 mg/kg/8 sem). Durée du suivi : 18 mois

BASDAI, moyenne (± ET) ASDAS, moyenne (± ET)

3,8 (0,2)

1,1 (0,1)

3,7 (0,4)

1,0 (0,2)

p ≥ 0,05

p ≥ 0,05





rhumatoïde o Spondylarthrite o Arthrite psoriasique o Colite ulcéreuse

n = 482 SA n = 91 BR/BR: n = 45 BR/BS: n = 46

Les sujets ont été maintenus sur l'infliximab BR (BR/BR) ou ont subi un changement de traitement, et ont été traités avec du BS CT-P13 (BR/BS).

ASDAS moyen (± ET) BASDAI moyen (± ET)

0,1 (0,6)

0,3 (1,0)

-0,2 (0,7)

-0,2 (1,4)

DRa : -0,01

(-0,27 à 0,24) p = N.D.

DRa : -0,02

(-0,50 à 0,47) p = N.D.

193

Auteur, (année),

pays (Période à

l’étude)


sites)






Résultats



(BR/BS)


o Maladie de Crohn o Psoriasis en plaques





Les doses et les intervalles de perfusion des sujets sont restés inchangés par rapport à ceux avant la randomisation et le changement de traitement Durée du suivi : 52 semaines

ETANERCEPT



Inclusion : Tous les sujets atteints PR, SA ou AP traités avec ETA BR. Exclusion : N.D. Pour SA Âge moyen (écart) BR/BR 48 (40-57) BR/BS 48 (39-57) Sexe Femme (% total): BR/BR : 34 (35 %) BR/BS : 115 (34 %)

SA n = 435 BR/BS n = 337 Sous-groupe BR/BS avec données pour ΔPreswitch = 117 ΔPostwitch = 168


Changement médian de ASDAS dans le temps (écart) Changement médian de BASDAI dans le temps (écart)

ΔPreswitch

−0,1 (−0,4 à 0,3)

0,0 (-8,0 à 6,0)

ΔPostswitch

0,1 (−0,2 à 0,6)

1,0 (-3,0 à 10,0)

S.O.

S.O.

194

Auteur, (année),

pays (Période à

l’étude)


sites)






Résultats



(BR/BS)


Tweehuysen (2018) Pays-Bas (Juin 2016-2017; cohorte historique, juin 2014)

Cohorte prospective et historique (1 site)

Inclusion : Sujets âgés de ≥ 18 ans atteints de PR, SA ou AP qui consent à changer pour le biosimilaire SB4. Exclusion : N.D. Pour toutes les indications Âge moyen ± ET BR/BR : 56 ± 14 ans BR/BS : 57 ± 14 ans Sexe Femme (% total) : BR/BR : 338 (56 %) BR/BS : 341 (55 %)

n = 1225 BR/BR (cohorte historique) n = 600 PR n = 422 SA n = 69 AP n = 109 BR/BS n = 625 PR n = 433 SA n = 64 AP n = 128

Changement de traitement du biologique de ETA BR vers SB4 BS (BR/BS) (même posologie, écart et appareil de distribution que le BR) Cohorte historique : sujets traités à l’ETA BR sans changement de traitement Durée du suivi : 6 mois

BASDAI moyen (± ET)

0,24 ± 0,23

0,30 ± 0,24

DRa : -0,08

(-0,90 à -0,74) p = N.D.

AP : Arthrite psoriasique; ASDAS : Questionnaire pour calculer l'index d'activité de la spondylarthrite ankylosante (Ankylosing Spondylitis Disease Activity Score); BASDAI : Questionnaire pour calculer l'index d'activité de la spondylarthrite ankylosante (Bath Ankylosing Spondylitis Disease Activity Index); BR : Biologique de référence; BS : Biosimilaire; DRa : Différence de risque ajustée; ECRA : Essai comparatif à randomisation aléatoire; ECRNA : Étude essais clinique à répartition non aléatoire; ET : Écart-type; IC : Intervalle de confiance; N.D. : Non disponible; PR :Ppolyarthrite rhumatoïde; SA : Spondylarthrite ankylosante; S.O. : Sans objet

195

Tableau E14 – Perte d’efficacité – Arthrite psoriasique

Auteur, (année),

pays (Période à

l’étude)


sites)

Critères d’inclusion et d’exclusion –Nombre et





Résultats


Changement de traitement (BR/BS)


INFLIXIMAB



Inclusion : Sujets atteints d’arthrite inflammatoire présent dans le registre DANBIO, plus 2 hôpitaux, qui ont changé de infliximab BR pour le BS CT-P13. Exclusion : N.D. Pour AP Âge médian (écart) : BR/BS : 52 (44-61) ans Sexe Femme (% total) : BR/BS : 58 (48 %)

n = 802 AP n = 120 BR/BS n = 120 Sous-groupe avec données pour ΔPreswitch = 78 ΔPostwitch = 81



ΔPreswitch

0,0 (−0,4 à 0,2)

ΔPostswitch

0,1 (−0,4 à 0,6)

p = 0,10

ETANERCEPT



Inclusion : Tous les sujets atteints PR, SA ou AP traités avec ETA BR. Exclusion : N.D. Pour AP Âge moyen (écart) : BR/BR : 52 (43-58) ans BR/BS : 52 (43-61) ans Sexe Femme (% total) : BR/BR : 31 (55 %) BR/BS : 160 (46 %)

AP n = 407 BR/BS n = 351 Sous-groupe BR/BS avec données pour ΔPreswitch = 158 ΔPostwitch = 152



ΔPreswitch

0,0 (0,0 à 0,0)

ΔPostswitch

0,1 (−0,4 à 0,5)

p = N.D.

AP : Arthrite psoriasique; BR : Biologique de référence; BS : Biosimilaire; DANBIO : Régistre nationale Danois; DAS28 : Score d’activité de la maladie en 28 points (Disease Activity Score); ECRNA : Étude essais clinique à répartition non aléatoire; ETA : Etanercept; IC : Intervalle de confiance; N.D. : Non disponible

196

Tableau E15 – Perte d’efficacité – Arthrite inflammatoire (PR, SA, AP)

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB










n = 482 PR n = 77 BR/BR n = 39 BR/BS n = 38 AP n = 30 BR/BR n = 14 BR/BS n = 16

Les sujets ont été maintenus sur l'infliximab BR (BR/BR) ou ont subi un changement de traitement, et ont été traités avec du BS CT-P13 (BR/BS). Les doses et les intervalles de perfusion des sujets sont restés inchangés par rapport à ceux avant la randomisation et le changement de traitement Durée du suivi : 52 semaines

Pathologies : PR, AP DAS28, moyenne (±ET)

0,3 (1,0)

0,1 (0,9)

DRa : 0,27 (-0,07 à 0,61)

p = N.D.

Vergara-Dangond (2017) Espagne


Inclusion : Sujets avec diagnostic de PR, SA ou AP traité et répondant à l’infliximab BR.

n = 13 BR/BS n = 7 BR/BR n = 6

Les sujets ont été maintenus sur l'infliximab BR (BR/BR) ou ont subi un changement de traitement et ont été

Pathologies : PR, SA, AP Rémission n/total (% total)

5/6 (83,3 %)

5/7 (71,4 %)

*p = 1,000

197

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


(Juin 2015 à janvier 2016)

Exclusion : N.D. Âge moyen ± ET : BR/BR : 53 ± 15 ans BR/BS : 49 ± 13 ans Sexe Homme (% total) : BR/BR : 6 (100 %) BR/BS : 5 (71 %)

traités avec le BS CT-P13 (BR/BS). Les doses de médicament à l'étude ont été optimisées individuellement au cours de l'étude selon le jugement du clinicien. Durée du suivi : 4 cycles de traitement

ETANERCEPT



Inclusion : Sujets âgés de ≥ 18 ans atteints de PR, SA ou AP qui consent à changer pour le biosimilaire SB4. Exclusion : N.D. Âge moyen ± ET BR/BR : 56 ± 14 ans BR/BS : 57 ± 14 ans Sexe Femme (% total) : BR/BR : 338 (56 %) BR/BS : 341 (55 %)

n = 1225 BR/BR n = 600 PR n = 422 SA n = 69 AP n = 109 BR/BS n = 625 PR n = 433 SA n = 64 AP n = 128

Changement de traitement du biologique de ETA BR vers SB4 BS (BR/BS) (même posologie, écart et appareil de distribution que le BR) Cohorte historique : sujets traités à l’ETA BR sans changement de traitement Durée du suivi : 6 mois

Pathologies : PR, AP Changement moyen de DAS28-CRP (± ET)

-0,26 ± 0,99

-0,01 ± 0,93

DRa = 0,15 (0,05 à 0,25)

p = N.D.

AP : Arthrite psoriasique; BR : Biologique de référence; BS : Biosimilaire; DRa : Différence de risque ajustée; ECRA : Essai comparatif à randomisation aléatoire; ET : Écart-type; IC : Intervalle de confiance; N.D. : Non disponible; PR :Ppolyarthrite rhumatoïde; SA : Spondylarthrite ankylosante

198


Tableau E16 – Immunogénicité – Polyarthrite rhumatoïde

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats




INFLIXIMAB






Exclusion : Traités précédemment avec infliximab ou des thérapies appauvrissant les lymphocytes. Âge moyen ± ET BR/BR 52,8 ± 12,9 ans BR/BS 52,8 ± 13,3 ans Sexe Femme (% total) : BR/BR : 264 (81,0 %) BR/BS : 258 (79,6 %)



n/total (% total) AAM positif AAMN positif

60/143 (42,0 %)

45/143

(31,5 %)

67/143 (46,9 %)

49/143

(34,3 %)

*p = 0,198

*p = 0,706







Exclusion : Troubles médicaux importants au cours des 54 premières semaines Âge moyen ± ET


Semaine 54 : Les sujets ont été maintenus sur l'infliximab (Remicade®) BR (BR/BR) ou ont subi un changement de traitement et ont été traités avec le biosimilaire SB2 (BR/BS). Perfusion intraveineuse de BR ou BS de 2 h à 3 mg/kg chaque 8 semaines. MTX (10–25 mg/sem) et acide folique (5–10 mg/sem)

AAM-positif n/total (% total) Nouveau AAM positif / AAM négatif au départ (% total) Nouveau AAMN positif / Nouveau AAM positif (% total)

51/101

(50,5 %)

7/47 (14,9 %)

5/7

(71,4 %)

43/94

(45,7 %)

6/41 (14,6 %)

2/6

(33,3 %)

*p = 0,567

*p = 1,000

*p = 0,286

199

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats




BR/BR 51,5 ± 11,2 ans BR/BS 53,0 ± 11,0 ans Sexe Femme (% total) : BR/BR : 79 (78,2 %) BR/BS :77 (81,9 %)


ADALIMUMAB







Âge moyen ± ET BR/BR 52,8 ± 12,3 ans BR/BS 51,7 ± 11,3 ans Sexe Femme (% total) : BR/BR : 103 (79,8 %) BR/BS : 105 (84,0 %)




26/126 (18,3 %)

11/87

(12,6 %)

21/125 (16,8 %)

5/80

(6,3 %)

*p = 0,518

*p = 0,194

Genovese (2019) 12 pays (Juin 2015 à janvier 2018)


Inclusion : - Adultes (≥18 ans) - Atteints de PR active - Dose stable de MTX (10-25 mg/sem) depuis ≥ 8 semaines et acide folique ≥5 mg/sem

Exclusion : - Traitement antérieur avec adalimumab BR ou BS

- Infections - TB active, VIH, Hépatite

Pour période II :

Semaines 0 à 24 Period I: n = 730 BR n = 363 BS n = 367 Semaines 24 à 54 Period II: n = 645 BR/BR n = 213 BR/BS n = 108

Semaine 24 Une portion des sujets a été maintenue sur le BR Adalimumab (BR/BR) ou a été traitée avec le BS FKB327 (BR/BS). L’autre portion des sujets a été maintenue sur le BS FKB327 (BS/BS) ou a été traitée avec le BR adalimumab (BS/BR) Injection sous cutanée de 40 mg FKB327 ou


98/190 (51,6 %)

42/93 (45,2 %)

*p = 0,315

Évaluation de control (BS/BS)

Changement de traitement (BS/BR)


200

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats




Âge moyen ± ET BR/BR 54,0 ± 12,6 ans BR/BS 52,3 ± 11,9 ans BS/BS 52,7 ± 12,4 ans BS/BR 52,1 ± 11,4 ans Sexe Femme (% total) : BR/BR : 171 (80,3 %) BR/BS : 83 (76,9 %) BS/BS : 162 (75,0 %) BS/BR : 85 (78,7 %)

BS/BS n = 216 BS/BR n = 108

d’adalimumab une fois aux 2 semaines Durée du suivi : 30 semaines


97/186 (52,2 %)

61/100 (61,0 %)

*p = 0,171

ETANERCEPT

Yamanaka (2020) Europe, Japon et Inde (Novembre 2015 à août 2017)


Inclusion : - Adultes (18 à 75 ans) - Atteints de PR - Dose stable de MTX (6-25 mg/sem) depuis ≥6 semaines

Exclusion : - Hypersensibilité à l’etanercept

- Infections - TB active - Allergies au latex Pour période II : Âge moyen (écart) BR 52,6 (18-74) ans BS 52,0 (22-75) ans Sexe Femme (% total) : BR : 208 (80.0 %) BS : 201 (76,1 %)

Semaines 0 à 24 Stage A, n = 528 Semaines 24 à 56 Stage B, n = 489 BR/BR: n = 235 BS/BS : n = 236 Stage C n = 18 BR/BS n = 10 BS/BR: n = 8

Semaine 28 Les sujets ont été maintenus sur le BR (BR/BR) ou le BS (BS/BS) ou ont inversés les traitements (BR/BS ou BS/BR). Injection sous cutanée de 50 mg de YLB113 ou BR une fois semaine plus methotrexate entre 6 mg et 25 mg par semaine Durée du suivi : 32 semaines


3/235 (18,3 %)

0/235

(12,6 %)

0/10 (16,8 %)

0/10

(6,3 %)

*p = 1,000

*p = 1,000





0/234 (0 %)

0/234 (0 %)

1/8

(12,5 %)

0/8 (0 %)

*p = 0,033

*p = 1,000

RITUXIMAB

Shim (2019) Europe, Asie du Pacifique, Amérique Latine



Semaines 0 à 48 N = 372 BR1 = 151 BR2 = 60 BS = 161

Semaine 48 Les sujets ont été maintenus sur le BR1 (BR/BR) ou ont changé de traitement vers BS (BR1/BS). Les sujets sur BR2 ont tous changé de

n/total (% total) AAM-positif

2/64 (3,1 %)

BR1/BS 8/62

(12,9 %)

BR2/BS 3/47

(6,4 %)

BR1/BS

*p = 0,052

BR2/BS

*p = 0,649

201

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats




(Août 2014 à janvier 2017)




Âge moyen ± ET BR1/BR1: 51,9 ± 10,3 ans BR1/BS : 52,3 ± 11,2 ans BR2/BS : 50,1 ± 10,7 ans Sexe Femme (% total) : BR1/BR1 : 54 (84,4 %) BR1/BS : 55 (88,7 %) BR2/BS : 40 (85,1 %)

Semaines 48 à 72 BR1/BR1 = 64 BR1/BS = 62 BR2/BS = 47 BS/BS = 120 BR1: EU-Rituximab BR2: UE-Rituximab BS: CT-P10

traitement au BS (BR2/BS) Chaque cycle comprenait deux perfusions intraveineuses de 1 g de CT-P10 ou Rituximab séparées par un intervalle de 2 semaines Durée du suivi : 24 semaines

Nouveau AAM-positif AAMN-positif

1/64 (1,6 %)

0/64 (0 %)

BR1/BS 1/62

(1,6 %)

BR2/BS 0/47 (0 %)

BR1/BS 0/62 (0 %)

BR2/BS

0/47 (0 %)

BR1/BS

*p = 1,000

BR2/BS

*p = 1,000

BR1/BS

S.O.

BR2/BS

S.O.

Tony (2019) États-Unis, Allemagne, Pologne, Hongrie (Juillet 2015 à octobre 2016)


Inclusion : - Adultes (≥ 18 ans) - Diagnostic de PR - Ayant reçu un traitement complet de Rituximab de 6 à 18 mois avant la randomisation

- Éligible à un autre traitement selon médecin

- Dose stable de MTX et d’acide folique depuis ≥4 semaines

Exclusion : - Grossesse, allaitement - PR : État fonctionnel de classe IV

- Hypersensibilité sévère au rituximab

- Infection systémique active

Âge moyen ± ET BR/BR 57,1 ±12,1 ans BR/BS 56,8 ± 9,9) ans

n = 107 BR/BR n = 54 BR/BS n = 53

Les sujets ont été maintenus sur le rituximab BR (BR/BR) ou ont subi un changement de traitement et ont été traités avec le BS GP2013 (BR/BS). Deux perfusions intraveineuses de 1 g de BS ou BR séparées par un intervalle de 2 semaines Tous les sujets ont reçu une dose stable de MTX (7,5-25 mg/sem) et d'acide folique. Durée du suivi : 24 semaines

n/total (% total) AAM positif Nouveau AAM positif AAMN positif

1/53 (1,9 %)

1/53 (1,9 %)

0/53 (0 %)

0/53 (0 %)

0/53 (0 %)

0/53 (0 %)

DR : -1,9 (-21,2 à 17,6)

p = N.D.

*p = 1,000

S.O.

202

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats




Sexe Femme (% total) : BR/BR : 39 (72,2 %) BR/BS : 46 (86,8 %)

AAM : Anticorps anti-médicament; AAMN : Anticorps anti-médicament neutralisants; TNF : Facteur de nécrose tumorale; BR : Biologique de référence; BS : Biosimilaire; DR : Différence de risque; ECRA : Essai comparatif à randomisation aléatoire; ET : Écart-type; IC : Intervalle de confiance; MTX : Méthotrexate; N.D. : Non disponible; PR : Polyarthrite rhumatoïde; RTX : Rituximab; S.O. : Sans objet; UE : Union européenne; EU : États-Unis * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

203

E.2.3 Innocuité

Tableau E17 – Innocuité – Polyarthrite rhumatoïde

Auteur, (année),

pays (Période à

l’étude)


sites)

Critères d’inclusion et d’exclusion –Nombre


Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB






Exclusion : Traités précédemment avec infliximab ou des thérapies appauvrissant les lymphocytes. Âge moyen ± ET BR/BR 52,8 ± 12,9 ans BR/BS 52,8 ± 13,3 ans Sexe Femme (% total): BR/BR : 264 (81,0 %) BR/BS : 258 (79,6 %)



n/total (% total) EIAT EIAT-relié au traitement EIGAT EIGAT-reliée au traitement EIAT causant l’arrêt du traitement EIAT-relié au traitement causant l’arrêt du traitement

48/143 (33,6 %)

20/143

(14,0 %)

11/143 (7,7 %)

5/143

(3,5 %)

10/143 (7,0 %)

7/143

(4,9 %)

54/143 (37,8 %)

16/143

(11,2 %)

4/143 (2,8 %)

0/143 (0 %)

7/143

(4,9 %)

5/143 (3,5 %)

*p = 0,537

*p = 0,537

*p = 0,109

*p = 0,060

*p = 0,468

*p = 0,770







Exclusion : Troubles médicaux importants au cours


Semaine 54 : Les sujets ont été maintenus sur l'infliximab (Remicade®) BR (BR/BR) ou ont subi un changement de traitement et ont été traités avec le biosimilaire SB2 (BR/BS). Perfusion intraveineuse de BR ou BS de 2 h à 3 mg/kg chaque 8 semaines. MTX (10–25 mg/sem) et acide folique (5–10 mg/sem)

n/total (% total) EI EIG EI causant l’arrêt du traitement Effets indésirables graves : - Infection - Réactions au site d’injection

36/101 (35,6 %)

3/101 (3,0 %)

1/101 (1,0 %)

34/94 (36,2 %)

6/94 (6,4 %)

3/94 (3,2 %)

*p = 1,000

*p = 0,318

*p = 0,359

204

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


des 54 premières semaines Âge moyen ± ET BR/BR 51,5 ± 11,2 ans BR/BS 53,0 ± 11,0 ans Sexe Femme (% total): BR/BR : 79 (78,2 %) BR/BS :77 (81,9 %)


- Malignité

ADALIMUMAB





Exclusion : - Traités précédemment avec adalimumab ou > 1 autres médicaments biologiques




Semaine 24 : Les sujets ont été maintenus sur l’adalimumab (Humira®) BR (BR/BR) ou ont subi un changement de traitement et ont été traités avec le BS BI 695501 (BR/BS). Humira® ou BI 695501 : 40 mg sous cutané par seringue préremplies une fois toutes les 2 semaines. Dose stable de MTX (15-25 mg/sem) Durée du suivi : 24 semaines

n/total (% total) EIAT EIAT-relié au traitement EIGAT EIGAT-relié au traitement EIAT causant l’arrêt du traitement

51/148 (34,5 %)

17/148

(11,5 %)

5/148 (3,4 %)

2/148

(1,4 %)

1/148 (0,7 %)

62/146 (42,5 %)

17/146

(11,6 %)

6/146 (4,1 %)

0/146 (0 %)

6/146

(4,1 %)

*p = 0,187

*p = 1,000

*p = 0,769

*p = 0,498

*p = 0,066

Weinblatt (2018)

ECRA Double-insu

Inclusion : - Adultes (18 à 75 ans)

Semaines 0 à 24

Semaine 24 : n/total (% total)

205

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


7 pays (Mai 2014 à avril 2015)

Groupes parallèles (51 sites)

- PR active, modérée à sévère depuis ≥ 6 mois

- Dose stable de MTX (10-25 mg/sem) depuis ≥4 semaines]




n = 544 BR n = 254, BS n = 271 Semaine 24 à 52 BR/BR n = 129 BR/BS n = 125 BS/BS n = 254

Les sujets ont été maintenus sur l’adalimumab (Humira®) BR (BR/BR) ou ont subi un changement de traitement et ont été traités avec le BS SB5 (BR/BS). Humira® ou SB5 : 40 mg sous cutané toutes les 2 semaines Durée du suivi : 28 semaines

EIAT EIGAT EIAT causant l’arrêt du traitement Effets indésirables graves : - Infection - Réactions au site d’injection - Malignité

42/127 (33,1 %)

4/127

(3,1 %)

3/127 (2,4 %)

47/125 (37,6 %)

4/125

(3,2 %)

2/125 (1,6 %)

*p = 0,510

*p = 1,000

*p = 1,000

ETANERCEPT

Yamanaka (2020) Europe, Japon et Inde (Novembre 2015 à août 2017)


Inclusion : - Adultes (18 à 75 ans) - Atteints de PR - Dose stable de MTX (6-25 mg/sem) depuis ≥6 semaines

Exclusion : - Hypersensibilité à l’etanercept

- Infections - TB active - Allergies au latex Pour période II : Âge moyen (écart) BR 52,6 (18-74) ans BS 52,0 (22-75) ans Sexe Femme (% total) : BR : 208 (80.0 %)

Semaines 0 à 24 Stage A, n = 528 Semaines 24 à 56 Stage B, n = 489 BR/BR: n = 235 BS/BS : n = 236 Stage C, n = 18 BR/BS n = 10 BS/BR: n = 8

Semaine 28 Les sujets ont été maintenus sur le BR (BR/BR) ou le BS (BS/BS) ou ont inversés les traitements (BR/BS ou BS/BR). Injection sous cutanée de 50 mg de YLB113 ou BR une fois semaine plus methotrexate entre 6 mg et 25 mg par semaine Durée du suivi : 32 semaines


146/235 (62,1 %)

62/235 (26,4 %

5/235

(2,1 %)

1/235 (0,4 %)

4/235

(1,7 %)

3/10 (30,0 %)

1/10

(10,0 %)

0/10 (0 %)

0/10 (0 %)

0/10 (0 %)

*p = 0,052

*p = 0,460

*p = 1,000

*p = 1,000

*p = 1,000

206

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


BS : 201 (76,1 %)




(BS/BR)


124/236 (52,5 %)

28/236

(11,9 %)

8/236 (3,4 %)

4/236

(1,7 %)

4/236 (1,7 %)

3/8 (37,5 %)

2/8

(25,0 %)

0/8 (0 %)

0/8

(0 %)

0/8 (0 %)

*p = 0,486

*p = 0,256

*p = 1,000

*p = 1,000

*p = 1,000

RITUXIMAB







Âge moyen ± ET BR1/BR1: 51,9 ± 10,3 ans

Semaines 0 à 48 n = 372 BR1 = 151 BR2 = 60 BS = 161 Semaines 48 à 72 BR1/BR1 = 64 BR1/BS = 62 BR2/BS = 47 BS/BS = 120 BR1: EU-Rituximab BR2:

Semaine 48 Les sujets ont été maintenus sur le BR1 (BR/BR) ou ont changé de traitement vers BS (BR1/BS). Les sujets sur BR2 ont tous changé de traitement au BS (BR2/BS) Chaque cycle comprenait deux perfusions intraveineuses de 1 g de CT-P10 ou Rituximab séparées par un intervalle de 2 semaines Durée du suivi : 24 semaines

n/total (% total) EIAT EIAT-relié au traitement EIGAT

21/64 (32,8 %)

13/64 (20,3 %)

0/64 (0 %)

BR1/BS 26/62

(41,9 %)

BR2/BS 10/47

(21,3 %)

BR1/BS 14/62

(22,6 %)

BR2/BS 4/47

(8,5 %)

BR1/BS 1/62

(1,6 %)

BR2/BS

*p = 0,358

*p = 0,205

*p = 0,830

*p = 0,112

*p = 0,492

207

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


BR1/BS : 52,3 ± 11,2 ans BR2/BS : 50,1 ± 10,7 ans Sexe Femme (% total): BR1/BR1 : 54 (84,4 %) BR1/BS : 55 (88,7 %) BR2/BS : 40 (85,1 %)

UE-Rituximab BS: CT-P10

EIGAT-relié au traitement EIAT causant l’arrêt du traitement Effets indésirables graves :

- Anémie - Leucopénie

0/64 (0 %)

0/64 (0 %)

0/47 (0 %)

BR1/BS 1/62

(1,6 %)

BR2/BS 0/47 (0 %)

BR1/BS 0/62 (0 %)

BR2/BS 0/47 (0 %)

S.O.

*p = 0,492

S.O.

S.O

S.O.

Tony (2019) États-Unis, Allemagne, Pologne, Hongrie (Juillet 2015 à octobre 2016)


Inclusion : - Adultes (≥ 18 ans) - Diagnostic de PR - Ayant reçu un traitement complet de Rituximab de 6 à 18 mois avant la randomisation

- Éligible à un autre traitement selon médecin

- Dose stable de MTX et d’acide folique depuis ≥4 semaines

Exclusion : - Grossesse, allaitement

- PR : État fonctionnel de classe IV

- Hypersensibilité sévère au rituximab

- Infection systémique active

n = 107 BR/BR n = 54 BR/BS n = 53

Les sujets ont été maintenus sur le rituximab BR (BR/BR) ou ont subi un changement de traitement et ont été traités avec le BS GP2013 (BR/BS). Deux perfusions intraveineuses de 1 g de BS ou BR séparées par un intervalle de 2 semaines Tous les sujets ont reçu une dose stable de MTX (7,5–25 mg/sem) et d'acide folique. Durée du suivi : 24 semaines

n/total (% total) EI EI-relié au traitement EIG EI causant l’arrêt du traitement Effets indésirables graves :

- Réactions d'hypersensibilité - Réactions liées à la perfusion

28/54 (51,9 %)

11/54

(20,4 %)

3/54 (5,6 %)

0/54 (0 %)

37/53 (69,8 %)

6/53

(11,3 %)

0/53 (0 %)

1/53

(1,9 %)

*p = 0,075

*p = 0,291

*p = 0,243

*p = 0,495

208

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


Âge moyen ± ET BR/BR 57,1 ±12,1 ans BR/BS 56,8 ± 9,9) ans Sexe Femme (% total) : BR/BR : 39 (72,2 %) BR/BS : 46 (86,8 %)

BR : Biologique de référence; BS : Biosimilaire; ECRA : Essai comparatif à randomisation aléatoire; EI : Effets indésirables; EIAT : Effets indésirables apparus en cours de traitement; EIG : Effets indésirables graves; EIGAT: Effets indésirables graves apparus en cours de traitement; ET : Écart-type; IC : Intervalle de confiance; MTX : Méthotrexate; PR : Polyarthrite rhumatoïde; S.O. : Sans objet * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

209

Tableau E18 – Innocuité – Spondylarthrite ankylosante

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB






n = 88 BR/BR n = 43 BR/BS n = 45


n/total (% total) EIG EI causant l’arrêt du traitement

0/43

0/43

0/45

0/45

S.O.

S.O.

BR : Biologique de référence; BS : Biosimilaire; EI : Effets indésirables; EIG : Effets indésirables graves; ET : Écart-type; IC : Intervalle de confiance; SA : Spondylarthrite ankylosante; S.O. : Sans objet

210

Tableau E19 – Innocuité – Arthrite inflammatoire (PR, SA, AP)

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB

Vergara-Dangond (2017) Espagne (Juin 2015 à janvier 2016)


Inclusion : Sujets avec diagnostic de PR, SA ou AP traité et répondant à l’infliximab BR. Exclusion : N.D. Âge moyen ± ET : BR/BR : 53 ± 15 ans BR/BS : 49 ± 13 ans Sexe Homme (% total) : BR/BR : 6 (100 %) BR/BS : 5 (71 %)

n = 13 BR/BS n = 7 BR/BR n = 6

Les sujets ont été maintenus sur l'infliximab BR (BR/BR) ou ont subi un changement de traitement et ont été traités avec le BS CT-P13 (BR/BS). Les doses de médicament à l'étude ont été optimisées individuellement au cours de l'étude selon le jugement du clinicien. Durée du suivi : 4 cycles de traitement

Pathologies : PR, SA, AP n/total (% total) EI EIG EI causant l’arrêt du traitement Effets indésirables graves :

- Dermatite

3/6 (50 %)

1/6

(16.7 %)

1/6 (16,7 %)

4/7 (57,1 %)

0/7

(0 %)

0/7 (0 %)

*p = 1,000

*p = 0,462

*p = 0,462

ETANERCEPT



Inclusion : Tous les sujets atteints PR, SA ou AP traités avec ETA BR. Exclusion : N.D. Âge moyen (écart) BR/BR 62 (48-70) ans BR/BS 61 (49-70) ans Sexe Femme (% total): BR/BR : 217 (76 %) BR/BS : 689 (74 %)

n = 2061 BR/BR n = 440 BR/BS n = 1621

Changement de traitement de l'ETA BR au BS (SB4) selon la posologie recommandée (BR/BS). Durée du suivi : Médian (écart) BR/BS : 383 (314–414) jours

Pathologies : PR, SA, AP n/total (% total) EI provoquant l’arrêt du traitement

14/440 (3,2 %)

77/1621 (4,8 %)

*p = 0,190

Tweehuysen (2018) Pays-Bas (Juin 2016-2017; cohorte


Inclusion : Sujets âgés de ≥ 18 ans atteints de PR, SA ou AP qui consent à changer pour le biosimilaire SB4. Exclusion : N.D.

n = 1225 BR/BR n = 600 PR n = 422 SA n = 69 AP n = 109

Changement de traitement du biologique de ETA BR vers SB4 BS (BR/BS) (même posologie, écart et appareil de distribution que le BR)

Pathologies : PR, AP EI causant l’arrêt du traitement, n/total (% total)

13/600 (2,2 %)

28/625 (4,5 %)

*p = 0,0263

211

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


historique, juin 2014)

Âge moyen ± ET BR/BR : 56 ± 14 ans BR/BS : 57 ± 14 ans Sexe Femme (% total) : BR/BR : 338 (56 %) BR/BS : 341 (55 %)

BR/BS n = 625 PR n = 433 SA n = 64 AP n = 128

Cohorte historique : sujets traités à l’ETA BR sans changement de traitement Durée du suivi : 6 mois

EI/sujet, median (écart) 1,0 (1–1);

1,5 (1–3)

p = 0,01

AP : Arthrite psoriasique; BR : Biologique de référence; BS : Biosimilaire; ECRNA : Étude essais clinique à répartition non aléatoire; EI : Effets indésirables; EIG : Effets indésirables graves; ET : Écart-type; ETA : Etanercept; IC : Intervalle de confiance; MTX : Méthotrexate; N.D. : Non disponible; PR : Polyarthrite rhumatoïde; SA : Spondylarthrite ankylosante; S.O. : Sans objet * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

212

E.2.4 Rétention

Tableau E20 – Rétention – Polyarthrite rhumatoïde

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats




INFLIXIMAB







Exclusion : Troubles médicaux importants au cours des 54 premières semaines Âge moyen ± ET BR/BR 51,5 ± 11,2 ans BR/BS 53,0 ± 11,0 ans Sexe Femme (% total): BR/BR : 79 (78,2 %) BR/BS :77 (81,9 %)


Semaine 54 : Les sujets ont été maintenus sur l'infliximab (Remicade®) BR (BR/BR) ou ont subi un changement de traitement et ont été traités avec le biosimilaire SB2 (BR/BS). Perfusion intraveineuse de BR ou BS de 2 h à 3 mg/kg chaque 8 semaines. MTX (10–25 mg/sem) et acide folique (5–10 mg/sem) Durée du suivi : 24 semaines

n/total (% total) Rétention Raisons (n/total arrêté) :

- EI - Retrait du consentement - Discrétion du clinicien - Perdu au suivi

96/101 (95,0 %)

1/5 1/5 1/5 2/5

88/94 (93,6 %)

3/6 2/6 0/6 1/6

*p = 0,761

S.O. S.O. S.O. S.O.

ADALIMUMAB





Exclusion : - Traités précédemment avec adalimumab ou >

Semaines 0 à 24 n = 645 BR n = 321 BS n = 324 Semaines 24 à 48 n = 593

Semaine 24 : Les sujets ont été maintenus sur l’adalimumab (Humira®) BR (BR/BR) ou ont subi un changement de traitement et ont été traités avec le BS BI 695501 (BR/BS).


140/148 (94,6 %)

138/147 (93,9 %)

*p = 0,809

213

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats




1 autres médicaments biologiques



BR/BR n = 148 BR/BS n = 147 BS/BS n = 298

Humira® ou BI 695501 : 40 mg sous cutané par seringue préremplies une fois toutes les 2 semaines. Dose stable de MTX (15-25 mg/sem) Durée du suivi : 24 semaines










n/total (% total) Rétention Raisons (n/total arrêté) : - EI - Retrait du consentement - Perdu au suivi - Manque d’efficacité - Autres

124/129 (96,1 %)

3 1 0 1 0

117/125 (93,6 %)

2 4 0 1 1

*p = 0,405

S.O. S.O. S.O. S.O. S.O.

Yazici (2018) Turquie

Cohorte rétrospective (1 site)

Inclusion : - Adultes - Atteints de PR

N = 697 BR/BR n = 605

Les sujets ont été maintenus sur l’infliximab (Remicade®) BR (BR/BR) ou ont subi un


400/605 (66,1 %)

12/92 (13,0 %)

*p < 0,001

214

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats




(Décembre, 2010 à juin, 2016)

- Traités avec infliximab BR.

- Changement vers CT-P13 doit avoir eu lieu dans les 16 semaines après une réclamation d’infliximab

Exclusions : - Grossesse - Cancer pendant la période d’étude


BR/BS n = 92

changement de traitement et ont été traités avec le BS CT-P13 (BR/BS). Durée du suivi : Moyenne (±ET) BR/BR : 16,3 ± 2,3 mois BR/BS : 15,1 ± 2,1 mois

Genovese (2019) 12 pays (Juin 2015 à janvier 2018)


Inclusion : - Adultes (≥18 ans) - Atteints de PR active - Dose stable de MTX (10-25 mg/sem) depuis ≥ 8 semaines et acide folique ≥5 mg/sem

Exclusion : - Traitement antérieur avec adalimumab BR ou BS

- Infections - TB active, VIH, Hépatite

Pour période II : Âge moyen ± ET BR/BR 54,0 ± 12,6 ans BR/BS 52,3 ± 11,9 ans BS/BS 52,7 ± 12,4 ans BS/BR 52,1 ± 11,4 ans Sexe Femme (% total) :

Semaines 0 à 24 Period I: n = 730 BR n = 363 BS n = 367 Semaines 24 à 54 Period II: n = 645 BR/BR n = 213 BR/BS n = 108 BS/BS n = 216 BS/BR n = 108

Semaine 24 Une portion des sujets a été maintenue sur le BR Adalimumab (BR/BR) ou a été traitée avec le BS FKB327 (BR/BS). L’autre portion des sujets a été maintenue sur le BS FKB327 (BS/BS) ou a été traitée avec le BR adalimumab (BS/BR) Injection sous cutanée de 40 mg FKB327 ou d’adalimumab une fois aux 2 semaines Durée du suivi : 30 semaines


190/213 (89,2 %)

93/108 (86,1 %)

*p = 0,466





189/216 (87,5 %)

100/108 (92,6 %)

*p = 0,188

215

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats




BR/BR : 171 (80,3 %) BR/BS : 83 (76,9 %) BS/BS : 162 (75,0 %) BS/BR : 85 (78,7 %)

ETANERCEPT




PR n = 1219 BR/BR n = 286 BR/BS n = 933


RRIa pour le Taux de rétention : - BR/BS vs sans changement

- BR/BS vs cohorte historique

N.D.

N.D.

N.D.

N.D.

RRIa : 0,81 (0,59 à 1,11)

p = 0,18

RRIa : 1,76 (1,39 à 2,23) p < 0,0001

RITUXIMAB







Semaines 0 à 48 N = 372 BR1 = 151 BR2 = 60 BS = 161 Semaines 48 à 72 BR1/BR1 n = 64 BR1/BS n = 62 BR2/BS n = 47 BS/BS n = 120

Semaine 48 Les sujets ont été maintenus sur le BR1 (BR/BR) ou ont changé de traitement vers BS (BR1/BS). Les sujets sur BR2 ont tous changé de traitement au BS (BR2/BS) Chaque cycle comprenait deux perfusions intraveineuses de 1 g de CT-P10 ou Rituximab séparées par un intervalle de 2 semaines Durée du suivi :

n/total (% total) Rétention Raisons (n/total arrêté) : - Retrait du consentement

64/64 (100 %)

BR1/BS 60/62

(96,8 %)

BR2/BS 47/47

(100 %)

2/2

*p = 0,240

S.O.

216

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats




Âge moyen ± ET BR1/BR1: 51,9 ± 10,3 ans BR1/BS : 52,3 ± 11,2 ans BR2/BS : 50,1 ± 10,7 ans Sexe Femme (% total): BR1/BR1 : 54 (84,4 %) BR1/BS : 55 (88,7 %) BR2/BS : 40 (85,1 %)

BR1: EU-Rituximab BR2: UE-Rituximab BS: CT-P10

24 semaines

BR : Biologique de référence; BS : Biosimilaire; ECRA : Essai comparatif à randomisation aléatoire; EI : Effets indésirables; ECRNA : Étude essais clinique à répartition non aléatoire; ET : Écart-type; ETA : Etanercept; IC : Intervalle de confiance; RRI : Rapport de risque instantanée (hazard ratio); MTX : Méthotrexate; PR : Polyarthrite rhumatoïde; S.O. : Sans objet * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

217

Tableau E21 – Rétention – Spondylarthrite ankylosante

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB






n = 88 BR/BR n = 43 BR/BS n = 45


n/total (% total) Rétention Raisons (n/total arrêté) : - Effet nocébo - Infections récurrentes - Aggravation maladie

40/43 (93,0 %)

0/3 2/3 1/3

40/45 (88,9 %)

4/5 1/5 0/5

*p = 0,714

S.O. S.O. S.O.

ETANERCEPT




SA n = 435 BR/BR n = 98 BR/BS n = 337


RRIa pour le Taux de rétention : - BR/BS vs sans changement

- BR/BS vs cohorte historique

N.D.

N.D.

N.D.

N.D.

RRIa : 0,92 (0,50 à 1,73),

p = 0,82

RRIa : 2,37 (1,51 à 3,73),

p = 0,0002

AP : Arthrite psoriasique; BR : Biologique de référence; BS : Biosimilaire; ECRNA : Étude essais clinique à répartition non aléatoire; ET : Écart-type; ETA : Etanercept; IC : Intervalle de confiance; RRI : Rapport de risque instantanée (hazard ratio); PR : Polyarthrite rhumatoïde; SA : Spondylarthrite ankylosante; S.O. : Sans objet * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

218

Tableau E22 – Rétention – Arthrite psoriasique

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)

Critères d’inclusion et d’exclusion –

Nombre et caractéristiques des

participants

Nombre total de

participants (n)



Résultats




ETANERCEPT



Inclusion : Tous les sujets atteints PR, SA ou AP traités avec ETA BR. Exclusion : N.D. Pour AP Âge moyen (écart) : BR/BR : 52 (43-58) ans BR/BS : 52 (43-61) ans Sexe Femme (% total) : BR/BR : 31 (55 %) BR/BS : 160 (46 %)

AP n = 407 BR/BR n = 56 BR/BS n = 351


RRIa pour le Taux de rétention : - BR/BS vs sans

changement - BR/BS vs cohorte

historique

N.D.

N.D.

N.D.

N.D.

RRIa = 0,55 (0,28 à 1,07)

p = 0,079

RRIa = 2,15 (1,42 à 3,25) p = 0,0003

AP : Arthrite psoriasique; BR : Biologique de référence; BS : Biosimilaire; ECRNA : Étude essais clinique à répartition non aléatoire; ETA : Etanercept; IC : Intervalle de confiance; RRI : Rapport de risque instantanée (hazard ratio); PR : Polyarthrite rhumatoïde; SA : Spondylarthrite ankylosante

219

Tableau E23 – Rétention – Arthrite inflammatoire (PR, SA, AP)

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB



Inclusion : Sujets atteints d’arthrite inflammatoire présent dans le registre DANBIO, plus 2 hôpitaux, qui ont changé de infliximab BR pour le BS CT-P13. Exclusion : N.D. Âge médian (écart) : BR/BS : 55 (44-66) ans Sexe Femme (% total) : BR/BS : 412 (51 %)

n = 802 BR/BR : cohorte historique n = inconnu BR/BS n = 802

Changement de traitement de l'infliximab BR au BS (CT-P13) selon la posologie recommandée (BR/BS). Durée du suivi : médiane (écart) : 413 (339–442) jours

Pathologies : PR, SA, AP Taux de rétention à 1 an (IC à 95 %) Taux de rétention ajusté à 1 an (IC à 95 %) Risque d’arrêt de traitement

86,2 % (84,0 à 88,0)

86,8 %

(84,8 à 88,8)

84,1 % (81,3 à 86,5)

83,4 %

(80,8 à 86,2)

p = 0,22

p = 0,03

RRI :1,31 (1,02 à 1,68)

p = 0,03

Vergara-Dangond (2017) Espagne (Juin 2015 à janvier 2016)


Inclusion : Sujets avec diagnostic de PR, SA ou AP traité et répondant à l’infliximab BR. Exclusion : N.D. Âge moyen ± ET : BR/BR : 53 ± 15 ans BR/BS : 49 ± 13 ans Sexe Homme (% total) : BR/BR : 6 (100 %) BR/BS : 5 (71 %)

n = 13 BR/BS n = 7 BR/BR n = 6

Les sujets ont été maintenus sur l'infliximab BR (BR/BR) ou ont subi un changement de traitement et ont été traités avec le BS CT-P13 (BR/BS). Les doses de médicament à l'étude ont été optimisées individuellement au cours de l'étude selon le jugement du clinicien. Durée du suivi : 4 cycles de traitement

Pathologies : PR, SA, AP n/total (% total) Rétention Raisons (n/total arrêté) : - EI

6/7 (85, 7 %)

1/1

6/6 (100 %)

0/0

*p = 1,000

S.O.

Scherlinger (2018) France (Novembre 2015 à octobre 2016; cohorte


Inclusion : - Atteints de PR, SA ou AP

- Traités par infliximab BR, en monothérapie ou en association avec des csDMARD

- Traitement infliximab BR stable depuis ≥ 6 mois

n = 171 BR/BS n = 89 (PR : 14; SA : 63; AP : 12) Cohorte historique

Changement de traitement de l'infliximab (Remicade®) BR au biosimilaire CT-P13 BS selon la posologie recommandée. Durée du suivi : Médian (écart) : 33 (6-50) semaines

Pathologies : PR, SA, AP, n/total (% total) Rétention

72/82 (87,8 %)

64/89 (71,9 %)

*p = 0,013

220

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


historique 2013)

- Maladie contrôlée selon l'avis du médecin.

Exclusion : - Sujets atteints de MII Âge moyen ± ET BR : 50,7 ± 12,3 ans BR/BS : 50,5 ± 13,3 ans Sexe Homme (% total): BR : 36 (44 %) BR/BS : 51 (57 %)

BR n = 82 (SA :64; PR : 18)

ETANERCEPT



Inclusion : Tous les sujets atteints PR, SA ou AP traités avec ETA BR. Exclusion : N.D. Âge moyen (écart) BR/BR : N.D. BR/BS : N.D. Sexe Femme (% total): BR/BR : N.D. BR/BS : N.D.

n = 2061 BR/BR n = 440 BR/BS n = 1621


Pathologies : PR, SA, AP n/total (% total) Rétention Raisons (n/total arrêté) : - Manque d’efficacité - EI - Raisons multiples - Cancer - Rémission - Grossesse - Décès - Infection - Perdu au suivi - Opération - Autres - Non définies

295/440 (67,0 %)

48/145 14/145 1/145 11/145 10/145 3/145 15/145 8/145 9/145 1/145 18/145 7/145

1322/1621 (81,6 %)

137/299 77/299 9/299 6/299 8/299 4/299 9/299 3/299 1/299 2/299

14/299 29/299

*p < 0,0001

S.O. S.O. S.O. S.O. S.O. S.O. S.O. S.O. S.O. S.O. S.O. S.O.



Inclusion : Sujets âgés de ≥ 18 ans atteints de PR, SA ou AP qui consent à changer pour le biosimilaire SB4. Exclusion : N.D. Âge moyen ± ET BR/BR : 56 ± 14 ans

n = 1225 BR/BR n = 600 PR n = 422 SA n = 69 AP n = 109 BR/BS n = 625

Changement de traitement du biologique de ETA BR vers SB4 BS (BR/BS) (même posologie, écart et appareil de distribution que le BR) Cohorte historique : sujets traités à l’ETA BR

Pathologies : PR, AP n/total (% total) Rétention

552/598 (92,3 %)

551/611 (90,2 %)

*p = 0,222

221

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


BR/BS : 57 ± 14 ans Sexe Femme (% total) : BR/BR : 338 (56 %) BR/BS : 341 (55 %)

PR n = 433 SA n = 64 AP n = 128

sans changement de traitement Durée du suivi : 6 mois

AP : Arthrite psoriasique; BR : Biologique de référence; BS : Biosimilaire; ECRA : Essai comparatif à randomisation aléatoire; ECRNA : Étude essais clinique à répartition non aléatoire; ET : écart-type; ETA : Etanercept; IC : Intervalle de confiance; MTX : Méthotrexate; RRI : Rapport de risque instantanée (hazard ratio); PR : Polyarthrite rhumatoïde; SA : Spondylarthrite ankylosante; S.O. : Sans objet * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

222

E.3. Dermatologie


Tableau E24 – Perte d’efficacité – Psoriasis en plaque

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB




- Diagnostic clinique : o Polyarthrite rhumatoïde o Spondylarthrite o Arthrite psoriasique o Colite ulcéreuse o Maladie de Crohn o Psoriasis en plaques




Âge moyen ± ET: BR/BR :51,1 ± 11,3 ans BR/BS :53,2 ± 13,1 ans Sexe Femme (% total) : BR/BR : 1 (6 %) BR/BS : 4 (24 %)

n = 482 Ps n = 35 BR/BR n = 18 BR/BS n = 17


PASI moyen (± ET)

-0,5 (1,9)

-0,4 (1,9)

DRa : -0,28

(-1,10 à 0,55) p = N.D.

ADALIMUMAB

Papp (2017) Australie, Canada et Hongrie


Inclusion : - Adultes (18 à 75 ans) - Ps stable modéré à sévère depuis ≥ 6 mois

- Candidat à la thérapie systémique ou à la photothérapie ne répondant

Semaines 1 à 16 n = 350 BR n = 175 BS n = 175

Semaine 16 : Changement de traitement du BR vers le BS ou maintien du BR 80 mg adalimumab BR sous-cutanée au jour 1

n/total (% total) PASI 75

61/70 (87,1 %)

56/69 (81,2 %)

*p = 0,362

223

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


(Octobre 2013 à mars 2015)

pas adéquatement ou incapable de recevoir ou tolérer au moins 1 thérapie systémique conventionnelle

- Atteinte de ≥ 10 % de la surface corporelle

- Score PASI de ≥ 12 - PGA de gravité ≥ modérée. - Femmes en âge de procréer avec contraception.

- Absence de tuberculose active

Exclusion : - Psoriasis non plaqué ou d'origine médicamenteuse ou d‘autre affection cutanée

- Utilisation précédente d'adalimumab ou d’un BS, ou ≥ 2 produits biologiques pour le psoriasis

- Traitement au UVA ou UVB - Thérapies topiques (sauf stéroïdes et émollients topiques moins puissants) dans les 14 jours avant l'étude

- Traitement au laser à excimère et thérapies systémiques non biologiques dans les 28 jours avant l'étude;

- Usage d’ETA dans le mois précédant le dépistage; et tout autre agent anti-TNF ou ustekinumab dans les 3 mois avant le dépistage.

Age médian (écart): BR : 41 (33-56) ans BS : 46 (35-54) ans Sexe Homme (% total) : BR: 116 (66,3 %)

Semaines 16 à 52 n = 308 BR/BR n = 79 BR/BS n = 77 BS/BS n = 152

(semaine 1) et 40 mg à la semaine 2 et chaque 2 semaines Durée du suivi : 50 semaines

224

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


BS: 112 (64,0 %)

Hercogova (2020) Amérique du Nord, Amérique du Sud et Europe (Février 2016 à décembre 2017)


Inclusion : - Adultes - Diagnostic de Ps depuis ≥ 6 mois

- Ps actif modérée à sévère mais stable cliniquement

- Traité auparavant par photothérapie ou traitement systémique ou candidat à ces thérapies.

- PASI ≥12 - PGA ≥ 3 (échelle de 0 à 4) - ≥ 10% de la surface corporelle affectée par le Ps


Exclusion : - Thérapie topique contre le psoriasis ou photothérapie dans les 2 semaines suivant l'inclusion

- Utilisation antérieure de traitement des maladies auto-immunes

Âge moyen ± (écart): BR : 42,4 ± 11,8 ans BS : 44,8 ± 12,7 ans Sexe Homme (% total) : BR: 130 (68,1 %) BS: 136 (67,0 %)

Semaines 1 à 16 n = 443 BR n = 221 BS n = 222 Semaines 16 à 52 n = 416 BR/BR n = 101 BR/BS n = 101 BS/BS n = 214 Analyse per-protocole BR/BR n = 95 BR/BS n = 96

Semaine 16 : Les sujets ont été maintenus sur

l'adalimumab BR

(BR/BR) ou ont subi un changement de traitement, et ont été traités avec le BS MSB11022 (BR/BS). Le MSB11022 ou l'adalimumab BR a été administré à une dose initiale de 80 mg par voie sous-cutanée, suivi de 40 mg toutes les semaines suivantes Durée du suivi : 52 semaines

Changement moyen dans l’échelle PASI, % (± ET) Nombre de mois médian pour obtenir PASI 75 (IC à 95%)

-94,0 ± 9,7

2,5 (1,7 à 2,6)

-94,8 ± 9,7

1,6 (1,6 à 1,7)

p = N.D.

p = N.D.

BR : Biologique de référence; BS : Biosimilaire; DRa : Différence de risque ajustée; ECRA : Essai comparatif à randomisation aléatoire; ET : Écart-type; ETA : Etanercept; IC : Intervalle de confiance; N.D.: Non disponible; PASI : Indice utilisé pour exprimer la gravité du psoriasis (Psoriasis Area Severity Index); PGA : Physician Global Assessment; Ps : Psoriasis en plaques; TNF : Facteur de nécrose tumorale * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

225


Tableau E25 – Immunogénicité – Psoriasis en plaque

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)






Résultats



(BR/BS)


ADALIMUMAB

Papp (2017) Australie, Canada et Hongrie (Octobre 2013 à mars 2015)



- Candidat à la thérapie systémique ou à la photothérapie ne répondant pas adéquatement ou incapable de recevoir ou tolérer au moins 1 thérapie systémique conventionnelle









Semaine 16 : Changement de traitement du BR vers le BS ou maintien du BR 80 mg adalimumab BR sous-cutanée au jour 1 (semaine 1) et 40 mg à la semaine 2 et chaque 2 semaines Durée du suivi : 48 semaines

n/total (% total) AAM positif AAMN-positif

59/79 (74,7 %)

16/79

(20,3 %)

56/77 (72,7 %)

19/77

(24,7 %)

*p = 0,856

*p = 0,567

226

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)






Résultats



(BR/BS)



Age médian (écart): BR : 41 (33-56) ans BS : 46 (35-54) ans Sexe Homme (% total) : BR: 116 (66,3 %) BS: 112 (64,0 %)

Blauvelt (2018) Bulgarie, France, Slovaquie et États-Unis (Décembre 2013 à mars 2015)


Inclusion : - Adultes (≥ 18 ans) - Ps depuis ≥ 6 mois - Ps actif modérée à sévère mais stable cliniquement

- PASI ≥ 12, - IGA ≥ 3 - ≥ 10% de la surface corporelle affectée par le psoriasis en plaques

- Traitement avec une photothérapie antérieure ou une thérapie systémique contre le psoriasis, ou l'aptitude à de telles thérapies.

Exclusion : - Autres formes de psoriasis - Psoriasis d'origine médicamenteuse

Age moyen ± (écart): BR/BR : 48 ± 13,8 ans BR/BS : 47,6 ± 14,3 ans Sexe Homme (% total) : BR/BR: 81 (63,8 %) BR/BS: 34 (54,0 %)

TP1 (semaines 1 à 16) n = 465 BR n = 234; BS n = 231

TP2 + Extension (semaines 17 à 51) n = 379 BR/BR n = 127 BR/BS/BR/BS/BR n = 63

BS/BS n = 126 BS/BR/BS/BR/BS N = 63

TP2 + Extension : A la semaine 17, les sujets ont été maintenus sur

l'adalimumab BR

(BR/BR) ou sur le GP2017 BS (BS/BS) ou ont subi un changement de traitement entre le BS et le BR tous les 6 semaines jusqu’à la semaine 35 (total de 4 changements) et ont été maintenus 16 semaines sur le dernier changement de traitement. Le GP2017 ou l'adalimumab BR a été administré à une dose initiale de 80 mg par voie sous-cutanée, suivi de 40 mg toutes les semaines suivantes Durée du suivi : 51 semaines

n/total (% total) AAM positif AAM positif AAMN positif AAMN positif

BR/BR 55/122

(45,1 %)

BS/BS 44/123

(35,8 %)

BR/BR 47/122

(38,5 %)

BS/BS 38/123

(30,9 %)

BR/BS/BR/BS/BR

24/61 (39,3 %)

BS/BR/BS/BR/

BS 28/60

(47,0 %)

BR/BS/BR/BS/BR

24/61 (39,3 %)

BS/BR/BS/BR/

BS 21/60

(35,0 %)

*p = 0,528

*p = 0,197

*p = 1,000

*p = 0,615

Hercogova (2020)

ECRA Double-insu

Inclusion : - Adultes

Semaines 1 à 16 n = 443

Semaine 16 : n/total (% total)

227

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)






Résultats



(BR/BS)


Amérique du Nord, Amérique du Sud et Europe (Février 2016 à décembre 2017)

(69 sites)

- Diagnostic de Ps depuis ≥ 6 mois








BR n = 221 BS n = 222 Semaines 16 à 52 n = 416 BR/BR n = 101 BR/BS n = 101 BS/BS n = 214 Analyse per-protocole BR/BR n = 95 BR/BS n = 96

Les sujets ont été maintenus sur l'adalimumab BR (BR/BR) ou ont subi un changement de traitement, et ont été traités avec le BS MSB11022 (BR/BS). Le MSB11022 ou l'adalimumab BR a été administré à une dose initiale de 80 mg par voie sous-cutanée, suivie de 40 mg toutes les semaines suivantes Durée du suivi : 52 semaines

AAM positif AAMN positif

68/87 (78,2 %)

29/87

(33,3 %)

77/87 (88,5 %)

30/87

(34,5 %)

*p = 0,103

*p = 1,000

ETANERCEPT

Griffiths (2017) 12 pays (Juin 2013 à mars 2015)




- PASI ≥ 10 - IGA ≥ 3 (échelle de 0 à 4)

TP1 (semaines 1 à 12) n = 531 BR n = 267 BS n = 264 TP2 (semaines 12 à 30) n = 497 BR/BR n = 151

TP2 + Extension : A la semaine 12, les sujets ont été

maintenus sur l'ETA

BR (BR/BR) ou sur le GP2015 BS (BS/BS) ou ont subi un changement de traitement entre le BS et le BR tous les 6 semaines jusqu’à la semaine 30 (total de 3 changements)


- TP2 - Extension

- TP2 - Extension

AAMN positif

BR/BR 0 / 151 (0 %) 0/142 (0 %)

BS/BS

0/150 (0 %) 0/140 (0 %)

BR/BR

BR/BS/BR/BS 0/96 (0 %)

1/90 (1,1 %)

BS/BR/BS/BR 0/100 (0 %) 0/95 (0 %0

BR/BS/BR/BS

S.O. *p = 0,388

S.O. S.O.

228

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)






Résultats



(BR/BS)


- ≥ 10% de la surface corporelle affectée par le psoriasis en plaques

Exclusion : - Exposition antérieure à l'ETA

- Exposition aux antagonistes du TNF ou à d'autres agents immunomodulateurs biologiques dans les 6 mois

- Utilisation continue de : corticostéroïdes topiques ou thérapie aux ultraviolets

- Infections systémiques actives au cours des 2 semaines précédentes

- Tuberculose latente détectée

Âge moyen ± ET: BR : 42,7 ± 12,9 ans BS : 42,1 ± 12,3 ans Sexe Homme (% total) : BR : 172 (64,4 %) BS : 157 (59,5 %)

BR/BS/BR/BS n = 96 BS/BS n = 150 BS/BR/BS/BR n = 100 Extension (semaines 30 à 52) n = 467 BR/BR n = 142 BR/BS/BR/BS n = 90 BS/BS n = 140 BS/BR/BS/BR n = 95

et ont été maintenus 22 semaines sur le dernier changement de traitement. Solution pour injection sous-cutanée en seringue préremplie. Le médicament est administré à une dose de 50 mg deux fois par semaine pendant les 12 premières semaines et 50 mg une fois par semaine par la suite Durée du suivi : 52 semaines

- TP2 - Extension

- TP2 - Extension

0 / 151 (0 %) 0/142 (0 %)

BS/BS

0/150 (0 %) 0/140 (0 %)

0/96 (0 %) 0/90 (0 %)

BS/BR/BS/BR 0/100 (0 %) 0/95 (0 %0

S.O. S.O.

S.O. S.O.

AAM : Anticorps anti-médicament; AAMN : Anticorps anti-médicament neutralisant; BR : Biologique de référence; BS : Biosimilaire; ECRA : Essai comparatif à randomisation aléatoire; ET : Écart-type; ETA : Etanercept; IC : Intervalle de confiance; IGA : Investigator’s Global Assessment; PASI : Indice utilisé pour exprimer la gravité du psoriasis (Psoriasis Area Severity Index); PGA : Physician Global Assessment; Ps : Psoriasis en plaques; TNF : Facteur de nécrose tumorale; TP : Time period * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

229

E.3.3 Innocuité

Tableau E26 – Innocuité – Psoriasis en plaque

Auteur, (année),

pays (Période à

l’étude)


sites)


Nombre et caractéristiques des participants




Résultats



(BR/BS)


ADALIMUMAB



Inclusion : - Adultes (18 à 75 ans)

- Ps stable modéré à sévère depuis ≥ 6 mois



- Score PASI de ≥ 12

- PGA de gravité ≥ modérée.

- Femmes en âge de procréer avec contraception.



- Utilisation précédente



n/total (% total) EIAT EIAT-relié au traitement EIGAT EIGAT-relié au traitement EIAT causant l’arrêt du traitement EIAT-relié au traitement causant l’arrêt du traitement

52/79 (65,8 %)

18/79

(22,8 %)

4/79 (5,1 %)

1/79

(1,3 %)

1/79 (1,3 %)

1/79

(1,3 %)

54/77 (70,1 %)

20/77

(26,0 %)

4/77 (5,2 %)

1/77

(1,3 %)

3/77 (3,9 %)

2/77

(2,6 %)

*p = 0,609

*p = 0,711

*p = 1,000

*p = 1,000

*p = 0,364

*p = 0,618

230

Auteur, (année),

pays (Période à

l’étude)


sites)






Résultats



(BR/BS)


d'adalimumab ou d’un BS, ou ≥ 2 produits biologiques pour le psoriasis

- Traitement au UVA ou UVB

- Thérapies topiques (sauf stéroïdes et émollients topiques moins puissants) dans les 14 jours avant l'étude




Blauvelt (2018) Bulgarie, France,




TP2 + Extension : A la semaine 17, les sujets ont été maintenus

sur l'adalimumab BR

(BR/BR) ou sur le

n/total (% total) EI

BR/BR 71/127

(55,9 %)

BR/BS/BR/BS/ BR

29/63 (46,0 %)

BS/BR/BS/BR/

*p = 0,219

231

Auteur, (année),

pays (Période à

l’étude)


sites)






Résultats



(BR/BS)


Slovaquie et États-Unis (Décembre 2013 à mars 2015)

- PASI ≥ 12, - IGA ≥ 3 - ≥ 10% de la surface corporelle affectée par le psoriasis en plaques.


Exclusion : - Autres formes de psoriasis

- Psoriasis d'origine médicamenteuse




GP2017 BS (BS/BS) ou ont subi un changement de traitement entre le BS et le BR tous les 6 semaines jusqu’à la semaine 35 (total de 4 changements) et ont été maintenus 16 semaines sur le dernier changement de traitement. Le GP2017 ou l'adalimumab BR a été administré à une dose initiale de 80 mg par voie sous-cutanée, suivi de 40 mg toutes les semaines suivantes Durée du suivi : 51 semaines

EI EI-relié au traitement EI-relié au traitement EIG EIG EIGAT-relié au traitement EIGAT-relié au traitement EIAT causant l’arrêt du traitement EIAT causant l’arrêt du traitement Effets indésirables graves :

BS/BS 66/126

(52,4 %)

BR/BR 16/127

(12,6 %)

BS/BS 16/126

(12,7 %)

BR/BR

8/127 (6,3 %)

BS/BS

3/126

(2,4 %)

BR/BR

3/127 (2,4 %)

BS/BS

1/126

(0,8 %)

BR/BR

8/127 (6,3 %)

BS/BS

14/126

(11,1 %)

BS 36/63

(57,1 %)

BR/BS/BR/BS/ BR

10/63 (15,9 %)

BS/BR/BS/BR/

BS 9/63

(14,3 %)

BR/BS/BR/BS/ BR

4/63 (6,3 %)

BS/BR/BS/BR/

BS 2/63

(3,2 %)

BR/BS/BR/BS/ BR

2/63 (3,2 %)

BS/BR/BS/BR/

BS 0/63 (0 %)

BR/BS/BR/BS/

BR 6/63

(9,5 %)

BS/BR/BS/BR/ BS

5/63 (7,9 %)

*p = 0,643

*p = 0,654

*p = 0,821

*p = 1,000

*p = 1,000

*p = 1,000

*p = 1,000

*p = 0,556

*p = 0,612

232

Auteur, (année),

pays (Période à

l’étude)


sites)






Résultats



(BR/BS)


- éruption cutanée toxique - pneumonie - pneumonie nécrosante - cellulite - infection staphylococcique - hypersensibilité - pyrexie - tuberculose pulmonaire - pyélonéphrite

Hercogova (2020) Amérique du Nord, Amérique du Sud et Europe (Février 2016 à décembre 2017)


Inclusion : - Adultes - Diagnostic de Ps depuis ≥ 6 mois



- PASI ≥12 - PGA ≥ 3 (échelle de 0 à 4)

- ≥ 10% de la surface corporelle affectée par le Ps




Semaines 1 à 16 n = 443 BR n = 221 BS n = 222 Semaines 16 à 52 n = 416 BR/BR n = 101 BR/BS n = 101 BS/BS n = 214 Analyse per-protocole BR/BR n = 95 BR/BS n = 96


l'adalimumab BR

(BR/BR) ou ont subi un changement de traitement, et ont été traités avec le BS MSB11022 (BR/BS). Le MSB11022 ou l'adalimumab BR a été administré à une dose initiale de 80 mg par voie sous-cutanée, suivie de 40 mg toutes les semaines suivantes Durée du suivi : 66 semaines


92/119 (77,3 %)

41/119

(34,5 %)

8/119 (6,7 %)

5/119

(4,2 %)

6/101 (5,9 %)

76/101 (75,2 %)

33/101

(32,7 %)

5/101 (5,0 %)

0/101 (0 %)

4/101

(4,0 %)

*p = 0,752

*p = 0,886

*p = 0,776

*p = 0,064

*p = 0,748

233

Auteur, (année),

pays (Période à

l’étude)


sites)






Résultats



(BR/BS)



ETANERCEPT









- Utilisation continue de : corticostéroïdes

TP1 (semaines 1 à 12) n = 531 BR n = 267 BS n = 264 TP2 (semaines 12 à 30) n = 497 BR/BR n = 151 BR/BS/BR/BS n = 96 BS/BS n = 150 BS/BR/BS/BR n = 100 Extension (semaines 30 à 52) n = 467 BR/BR n = 142 BR/BS/BR/BS n = 90 BS/BS n = 140 BS/BR/BS/BR n = 95


sur l'ETA BR (BR/BR)

ou sur le GP2015 BS (BS/BS) ou ont subi un changement de traitement entre le BS et le BR tous les 6 semaines jusqu’à la semaine 30 (total de 3 changements) et ont été maintenus 22 semaines sur le dernier changement de traitement. Solution pour injection sous-cutanée en seringue préremplie. Le médicament est administré à une dose de 50 mg deux fois par semaine pendant les 12 premières semaines et 50 mg une fois par semaine par la suite Durée du suivi : 52 semaines

n/total (% total) EIAT EIAT EIAT-relié au traitement EIAT-relié au traitement EIG EIG EIAT menant à l’arrêt du traitement EIAT menant à l’arrêt du traitement

BR/BR 98/171

(57,3 %) BS/BS 98/164

(59,8 %)

BR/BR 33/171

(19.3 %) BS/BS 34/164

(20,7 %)

BR/BR 7/171

(4,1 %) BS/BS 7/164

(4,3 %)

BR/BR 8/171

(4,7 %) BS/BS 11/164 (6,7 %)

BR/BS/BR/BS

57/96 (59,4 %)

BS/BR/BS/BR 61/100

(61,0 %)

BR/BS/BR/BS 20/96

(20,8 %) BS/BR/BS/BR

22/100 (22,0 %)

BR/BS/BR/BS

6/96 (6,3 %)

BS/BR/BS/BR 6/100

(6,0 %)

BR/BS/BR/BS 5/96

(5,2 %) BS/BR/BS/BR

2/100 (2,0 %)

*p = 0,797

*p = 0,797

*p = 0,752

*p = 0,877

*p = 0,555

*p = 0,567

*p = 1,000

*p = 0,140

234

Auteur, (année),

pays (Période à

l’étude)


sites)






Résultats



(BR/BS)


topiques ou thérapie aux ultraviolets




BR : Biologique de référence; BS : Biosimilaire; ECRA : Essai comparatif à randomisation aléatoire; EI : Effets indésirables; EIAT : Effets indésirables apparus en cours de traitement; EIG : Effets indésirables graves; ET : Écart-type; ETA : Etanercept; IC : Intervalle de confiance; IGA : Investigator’s Global Assessment; PASI : Indice utilisé pour exprimer la gravité du psoriasis (Psoriasis Area Severity Index); PGA : Physician Global Assessment; Ps : Psoriasis en plaques; TNF : Facteur de nécrose tumorale; TP : Time period * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

235

E.3.4 Rétention

Tableau E27 – Rétention – Psoriasis en plaque

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)






Résultats



(BR/BS)


ADALIMUMAB














n/total (% total) Rétention Raisons (n/total arrêté) : - Discrétion du clinicien - Manque d’efficacité - EI - Abandon du sujet - Perdu au suivi

71/79 (89.9 %)

0/8 3/8 1/8 3/8 1/8

69/77 (89,6 %)

1/8 1/8 1/8 3/8 2/8

*p = 1,000

S.O. S.O. S.O. S.O. S.O.

236

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)






Résultats



(BR/BS)




Blauvelt (2018) Bulgarie, France, Slovaquie et États-Unis (Décembre 2013 à mars 2015)



- PASI ≥ 12, - IGA ≥ 3 - ≥ 10% de la surface corporelle affectée par le psoriasis en plaques.


Exclusion : - Autres formes de psoriasis - Psoriasis d'origine médicamenteuse






sur l'adalimumab BR

(BR/BR) ou sur le GP2017 BS (BS/BS) ou ont subi un changement de traitement entre le BS et le BR tous les 6 semaines jusqu’à la semaine 35 (total de 4 changements) et ont été maintenus 16 semaines sur le dernier changement de traitement. Le GP2017 ou l'adalimumab BR a été administré à une dose initiale de 80 mg par voie sous-cutanée, suivi de 40 mg toutes les semaines suivantes Durée du suivi : 51 semaines

n/total (% total) Rétention Rétention

BR/BR

104/127 (81,9 %)

BS/BS

100/126 (79,4 %)

BR/BS/BR/BS/

BR 47/63

(74,6 %)

BS/BR/BS/BR/ BS

50/63 (79,4 %)

*p = 0,257

*p = 1,000

Hercogova (2020)

ECRA Double-insu

Inclusion : - Adultes

Semaines 1 à 16 n = 443



90/101

90/101

*p = 1,000

237

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)






Résultats



(BR/BS)


Amérique du Nord, Amérique du Sud et Europe (Février 2016 à décembre 2017)

(69 sites) - Diagnostic de Ps depuis ≥ 6 mois








BR n = 221 BS n = 222 Semaines 16 à 52 n = 416 BR/BR n = 101 BR/BS n = 101 BS/BS n = 214 Analyse per-protocole BR/BR n = 95 BR/BS n = 96

l'adalimumab BR

(BR/BR) ou ont subi un changement de traitement, et ont été traités avec le BS MSB11022 (BR/BS). Le MSB11022 ou l'adalimumab BR a été administré à une dose initiale de 80 mg par voie sous-cutanée, suivie de 40 mg toutes les semaines suivantes Durée du suivi : 52 semaines

Raison (n/total arrêté) : - EI - Perdu au suivi - Non-respect du protocole - Manque d’efficacité - Retrait du consentement - Autres

(89,1 %)

6/11 1/11 0/11 2/11 2/11 0/11

(89,1 %)

4/11 1/11 1/11 2/11 2/11 1/11

S.O. S.O. S.O. S.O. S.O. S.O.

ETANERCEPT






TP1 (semaines 1 à 12) n = 531 BR n = 267 BS n = 264 TP2 (semaines 12 à 30) n = 497 BR/BR n = 151


sur l'ETA BR (BR/BR)

ou sur le GP2015 BS (BS/BS) ou ont subi un changement de traitement entre le BS et le BR tous les 6 semaines jusqu’à la semaine 30 (total de 3 changements) et ont été maintenus 22 semaines

n/total (% total) Rétention TP2 Extension TP2

BR/BR 142/151 (94,0 %)

137/142 (96,5 %)

BS/BS

143/150 (95,3 %)

BR/BS/BR/BS 91/96

(94,8 %)

90/90 (100 %)

BS/BR/BS/BR

96/100 (96,0 %)

*p = 1,000

*p = 0,159

*p = 1,000

238

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)






Résultats



(BR/BS)





- Utilisation continue de : corticostéroïdes topiques ou thérapie aux ultraviolets




BR/BS/BR/BS n = 96 BS/BS n = 150 BS/BR/BS/BR n = 100 Extension (semaines 30 à 52) n = 467 BR/BR n = 142 BR/BS/BR/BS n = 90 BS/BS n = 140 BS/BR/BS/BR n = 95

sur le dernier changement de traitement. Solution pour injection sous-cutanée en seringue préremplie. Le médicament est administré à une dose de 50 mg deux fois par semaine pendant les 12 premières semaines et 50 mg une fois par semaine par la suite Durée du suivi : 52 semaines

Extension

132/140 (94,3 %)

88/95 (92,6 %)

*p = 0,600

BR : Biologique de référence; BS : Biosimilaire; ECRA : Essai comparatif à randomisation aléatoire; EI : Effets indésirables; ET : Écart-type; ETA : Etanercept; IC : Intervalle de confiance; IGA : Investigator’s Global Assessment; PASI : Indice utilisé pour exprimer la gravité du psoriasis (Psoriasis Area Severity Index); PGA : Physician Global Assessment; Ps : Psoriasis en plaques; TNF : Facteur de nécrose tumorale; TP : Time period * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

239

E.4. Spécialités combinées (gastroentérologie, rhumatologie et dermatologie)


Tableau E28 – Immunogénicité – Spécialités combinées

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB









Âge moyen ± ET : BR/BR : 47,5 ± 14,8 ans BR/BS : 48,2 ± 14,9 ans Sexe Femme (% total) : BR/BR : 99 (41 %) BR/BS : 87 (36 %)

n = 482 BR/BR n = 241 BR/BS n = 241


Pathologies : AP, CU, MC, PR, Ps, SA n/total (% total) AAMN positif Nouveau AAMN positif

26/241 (10,7 %)

17/241 (7,1 %)

30/240 (12,5 %)

19/240 (7,9 %)

*p = 0,573

*p = 0,733

AAM : Anticorps anti-médicament; AAMN : anticorps anti-médicament neutralisant; AP : Arthrite psoriasique; BR : Biologique de référence; BS : Biosimilaire; CU : Colite ulcéreuse; ECRA : Essai comparatif à randomisation aléatoire; EI : Effets indésirables; ET : Écart-type; IC : Intervalle de confiance; MC : Maladie de Crohn; PR : Polyarthrite rhumatoïde; Ps : Psoriasis en plaques; SA : Spondylarthrite ankylosante * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

240

Tableau E29 – Innocuité – Spécialités combinées

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB










n = 482 BR/BR n = 241 BR/BS n = 241


Pathologies : PR, SA, AP, MC, CU, Ps n/total (% total) EI EIG EI causant l’arrêt du traitement Effets indésirables graves :

- Infarctus aigu du myocarde

- fibrillation auriculaire - décollement de la rétine - douleur abdominale - douleur de poitrine - cholécystite - abcès anal - gastro-entérite - pyélonéphrite - amygdalite - arthrite - cancer de la vessie - néphrolithiase - cholécystectomie - radiothérapie - opérations - embolie artérielle fémorale

168/241 (70 %)

24/241 (10 %)

9/241 (4 %)

164/240 (68 %)

21/240 (9 %)

8/240 (3 %)

*p = 0,768

*p = 0,755

*p = 1,000

AP : Arthrite psoriasique; BR : Biologique de référence; BS : Biosimilaire; CU : Colite ulcéreuse; ECRA : Essai comparatif à randomisation aléatoire; EI : Effets indésirables; EIG : Effets indésirables graves; ET : Écart-type; IC : Intervalle de confiance; MC : Maladie de Crohn; PR : Polyarthrite rhumatoïde; Ps : Psoriasis en plaques; SA : Spondylarthrite ankylosante * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php);

241

Tableau E30 – Rétention – Spécialités combinées

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


INFLIXIMAB










n = 482 BR/BR n = 241 BR/BS n = 241


n/total (% total) Rétention Raisons (n/total arrêté) : - Retrait du consentement - Manque d’efficacité - EI - Violation du protocole - Violation de l’éligibilité - Perdu au suivi - Autres raisons

216//241 (89,6 %)

6/25 8/25 8/25 0/25 0/25 1/25 2/25

222/241 (92,1 %)

5/19 3/19 6/19 2/19 1/19 0/19 2/19

*p = 0,429

S.O. S.O. S.O. S.O. S.O. S.O. S.O.

AP : Arthrite psoriasique; BR : Biologique de référence; BS : Biosimilaire; ECRA : Essai comparatif à randomisation aléatoire; EI : Effets indésirables; ET : Écart-type; IC : Intervalle de confiance; MC : Maladie de Crohn; PR : Polyarthrite rhumatoïde; Ps : Psoriasis en plaques; SA : Spondylarthrite ankylosante * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

242

E.5. Oncologie


Tableau E31 – Perte d’efficacité – Oncologie

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)



Nombre total de

participants (n)



Résultats


Changement de

traitement (BR/BS)


FILGRASTIM

Blackwell (2018) 6 pays (Décembre 2011 à juin 2013)


Inclusion : - Femme adulte (≥ 18 ans) - Cancer du sein confirmé histologiquement

- Éligible au traitement TAC (docétaxel, doxorubicine et cyclophosphamide)

- ECOG ≤ 2 - Fonction adéquate de la moëlle osseuse au jour 1

Exclusion : - Antécédent de leucémie myéloïde, de syndrome myélodysplasique ou de drépanocytose concomitante

- Radiothérapie concomitante ou antérieure depuis ≤ 4 semaines

- Utilisation d'antibiotiques prophylactiques,

- Chimiothérapie antérieure ou traitement anticancéreux du cancer du sein

- Traitement antérieur par G-CSF Âge moyen ± ET BR/BR : 46,9 ± 10,9 ans BR/BS : 48,6 ± 11,4 ans

n = 214 BR/BR n = 52 BS/BS n = 53 Groupe switch: n = 109 BR/BS/BR/BS/ BR/BS n = 55 BS/BR/BS/BR/ BS/BR n = 54

Les sujets ont été traités soit avec le BR filgrastim ou le BS EP2006 uniquement ou ont subi un changement de traitement entre le BS et le BR à chaque cycle de traitement pour un total de 6 cycles. Les BR ou BS ont été administrés (5 ug/kg/ jour) à partir du jour 2 de chaque cycle jusqu'à ce que le ANC soit revenu à 10x109/l après son nadir ou pendant un maximum de 14 jours. Durée du suivi : 6 cycles de chimiothérapie

Neutropénie fébrile, n/total (% total) Infection, incidence Temps de récupération de ANC entre les cycles de traitement :

2 3 4 5 6

0/46 (0 %)

9,9 %

N.D.

N.D.

N.D.

N.D.

N.D.

3 /87 (3,4 %)

9,3 %

N.D.

N.D.

N.D.

N.D.

N.D.

Différence : -3,4 (-9,65 à 4,96)

p = N.D.

Différence moyenne ajustée

(IC à 95 %)

-0,01 (-0,28 à 0,26)

0,26

(-0,01;0,53)

-0,02 (-0,29;0,25)

0,10

(-0,17;0,37)

0,01 (-0,26;0,29)

ANC : Nombre absolu de neutrophiles; BR : Biologique de référence; BS : Biosimilaire; ECRA : Essai comparatif à randomisation aléatoire; EGOG : Eastern Cooperative Oncology Group; ET : Écart-type; G-CSF : Facteur stimulant les colonies de granulocytes; IC : Intervalle de confiance; TAC : Traitement néo-adjuvant et adjuvant du cancer du sein; N.D. : Non disponible

243

Tableau E32 – Immunogénicité – Oncologie

Auteur, (année),

pays (Période à

l’étude)


sites)






Résultats



(BR/BS)


FILGRASTIM










- Traitement antérieur par G-CSF

Âge moyen ± ET BR/BR : 46,9 ± 10,9 ans BR/BS : 48,6 ± 11,4 ans



n/total (% total) AAMN positif

0/52 (0 %)

0/109 (0 %)

S.O.

AAM : Anticorps anti-médicament; AAMN : Anticorps anti-médicament neutralisants; ANC : Nombre absolu de neutrophiles; BR : Biologique de référence; BS : Biosimilaire; ECRA : Essai comparatif à randomisation aléatoire; EGOG : Eastern Cooperative Oncology Group; ET : Écart-type; G-CSF : Facteur stimulant les colonies de granulocytes; IC : Intervalle de confiance; TAC : Traitement néo-adjuvant et adjuvant du cancer du sein; S.O. : Sans objet

244

Tableau E33 – Innocuité – Oncologie

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)






Résultats




FILGRASTIM














n/total (% total) EIAT EIAT-relié au traitement EIGAT EI causant l’arrêt de traitement

49/51 (96,1 %)

20/51

(39,2 %)

1/51 (2,0 %)

0/51 (0 %)

102/107 (95,3 %)

45/107

(42,1 %)

5/107 (4,7 %)

0/107 (0 %)

*p = 1,000

*p = 0,863

*p = 0,665

S.O.

TRASTUZUMAB

Von Minckwitz (2019) 20 pays (Avril 2013 à septembre 2015)


Inclusion : - Femmes adultes (≥ 18 ans) - Cancer du sein invasif confirmé histologiquement

- ECOG < 2 - Résection chirurgicale planifiée avec dissection des ganglions sentinelles ou axillaires

Semaines 0 à 24 n = 725 BR n = 361 BS n = 364 Semaines 24 à 52

Semaines 24 à 52 Les sujets ont subi une chirurgie et ont soit été maintenus sur Trastuzumab BR (BR/BR) ou ont subi un changement de traitement et ont été traités avec le BS ABP980 (BR/BS).

n/total (% total) EI EIG

55/171 (32,2 %)

6/171

(3,5 %)

3/171

66/171 (38,6 %)

6/171

(3,5 %)

4/171

*p = 0,258

*p = 1,000

*p = 1,000

245

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)






Résultats




- Chimiothérapie néoadjuvante planifiée

- HER2-positif confirmé - Statut connu des récepteurs des œstrogènes et des récepteurs de la PG

Exclusion : - Cancer du sein bilatéral - Métastases distantes - Traitement antérieur du cancer du sein primaire, y compris la chimiothérapie, un agent biologique, la radiothérapie ou la chirurgie

- Tumeur maligne active concomitante

Âge moyen (intervalle) : BR/BS : 53 (44-62) ans BR/BR : 53 (45-60) ans Sexe, n (%) : Femmes seulement (100 %)



EI causant l’arrêt de traitement Effets indésirables graves :

- Infections - Neutropénie - Infestations - Réaction infusion

(1,8 %) (2,3 %)

ANC : Nombre absolu de neutrophiles; BR : Biologique de référence; BS : Biosimilaire; ECRA : Essai comparatif à randomisation aléatoire; EGOG : Eastern Cooperative Oncology Group; EI : Effets indésirables; EIAT : Effets indésirables apparus en cours de traitement; EIG : Effets indésirables graves; EIGAT : Effets indésirables graves apparus en cours de traitement ET : Écart-type; G-CSF : Facteur stimulant les colonies de granulocytes; HER : Human epidermal growth factor receptor; IC : Intervalle de confiance; PG : Progestérone; TAC : Traitement néo-adjuvant et adjuvant du cancer du sein; S.O. : Sans objet * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

246

Tableau E34 – Rétention – Oncologie

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)



Nombre total de

participants (n)



Résultats


Changement de

traitement (BR/BS)


FILGRASTIM














n/total (% total) Rétention Raison (n/total arrêté) : - Abandon du sujet - Perdu au suivi - Autres

48/54 (88,9 %)

2/6 1/6 3/6

95/110 (86,4 %)

6/15 3/15 6/15

*p = 0,805

S.O. S.O. S.O.

TRASTUZUMAB

Von Minckwitz (2019) 20 pays (Avril 2013 à septembre 2015)


Inclusion : - Femmes adultes (≥ 18 ans) - Cancer du sein invasif confirmé histologiquement

- ECOG < 2 - Résection chirurgicale planifiée avec dissection des ganglions sentinelles ou axillaires

Semaines 0 à 24 n = 725 BR n = 361 BS n = 364 Semaines 24 à 52

Semaines 24 à 52 Les sujets ont subi une chirurgie et ont soit été maintenus sur Trastuzumab BR (BR/BR) ou ont subi un changement de traitement et ont été traités avec le BS ABP980 (BR/BS).


164/171 (96,0 %)

157/171 (91,8 %)

*p = 0,175

247

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)



Nombre total de

participants (n)



Résultats


Changement de

traitement (BR/BS)


- Chimiothérapie néoadjuvante planifiée

- HER2-positif confirmé - Statut connu des récepteurs des œstrogènes et des récepteurs de la PG

Exclusion : - Cancer du sein bilatéral - Métastases distantes - Traitement antérieur du cancer du sein primaire, y compris la chimiothérapie, un agent biologique, la radiothérapie ou la chirurgie

- Tumeur maligne active concomitante

Âge moyen (intervalle) : BR/BS : 53 (44-62) ans BR/BR : 53 (45-60) ans Sexe, n (%) : Femmes seulement (100 %)



ANC : Nombre absolu de neutrophiles; BR : Biologique de référence; BS : Biosimilaire; ECRA : Essai comparatif à randomisation aléatoire; EGOG : Eastern Cooperative Oncology Group; ET : Écart-type; G-CSF : Facteur stimulant les colonies de granulocytes; HER : Human epidermal growth factor receptor; IC : Intervalle de confiance; PG : Progestérone; TAC : Traitement néo-adjuvant et adjuvant du cancer du sein; S.O. : Sans objet * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

248

E.6. Endocrinologie


Tableau E35 – Perte d’efficacité – Diabète

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de participants

(n)



Résultats



(BR/BS)


INSULINE

Blevins (2019) 8 pays (Décembre 2015 à mars 2017)

ECRA Ouverte (81 sites)

Inclusion : - Adulte (18 à 65 ans) - Diagnostic de diabète de type 1

- Avoir suivi avec succès, 52 semaines de traitement à l'insuline glargine de référence dans l'étude INSTRIDE 1

Exclusion : - Antécédent d'infections cliniquement significatives,

- Résistance à l'insuline modérée (nécessitant une insuline basale plus prandiale ≥1,5 U/kg/j),

- Chirurgie élective prévue et nécessitant une hospitalisation

- Autre médicament expérimental

Âge moyen ± ET BR/BR 43,2 (12,7) BR/BS 44,8 (11,4) Homme (% total): BR/BR : 36 (57,1) BR/BS : 41 (64,1)

n = 127 BR/BR n = 63 BR/BS/BR/BS n = 64

Les patients ont soit été maintenus sur l'insuline glargine BR (BR/BR) ou ont subi un changement de traitement toutes les 12 semaines en alternant entre le BS MYL1501D et le BR (BR/BS/BR/BS). Les deux traitements ont été administrés sous forme d'injections sous-cutanées, avec des doses d'étude initiales de MYL-1501D et de l'insuline glargine BR administrées à une dose adaptée aux niveaux réels de glucose dans le sang des participants. Durée du suivi : 36 semaines

Différence en HbA1c par rapport au niveau de base dans la moyenne des moindres carrés, % (± ET) Dose basale quotidienne moyenne d’insuline, U/kg (± ET)

−0,06 (0,034)

0,36 (0,17)

BR/BS/BR/BS

−0,05 (0,032)

BR/BS/BR/BS

0,32 (0,13)

Différence : 0,01 (−0,085 à 0,101),

p > 0,05

p = N.D.

Hadjivianni (2016) Élément 1 : 9 pays

Analyse post-hoc de 2 ECRA Élément 1 (52 sites)

Inclusion : Élément 1 : - Adultes (≥ 18 ans) - Diabète type 1 depuis ≥ 1 an - Insulinothérapie à bolus-

basal depuis ≥ 1 an

n = 750 BR/BR : Élément 1 n = 234

Les sujets ont été maintenus sur l’insuline IGlar BR (BR/BR) ou ont subi un changement de traitement et ont été traités avec le

Différence en HbA1c par rapport au niveau de base dans la moyenne des moindres carrés :

Différence : -0,018

249

Auteur, (année),

pays (Période à

l’étude)


sites)




(n)



Résultats



(BR/BS)


(2001-2013) - HbA1c ≤ 11,0 % - IMC ≤ 35 kg/m2. Exclusion : Élément 1 : - Usage de IGlar BS, anti-

hyperglycémiants oraux, IGlar deux fois par jour, pramlintide ou perfusion d'insuline sous-cutanée continue,

- Dose quotidienne totale d'insuline ≥ 1,5 U/kg

- ≥ 1 épisode d'hypoglycémie sévère ou une visite aux urgences ou hospitalisation pour mauvais contrôle de la glycémie ≤ 6 derniers mois.

Element-1 Âge moyen ± ET BR/BR 41 ± 13 ans BR/BS 41 ± 14 ans Sexe Homme (% total): BR/BR: 137 (59) BR/BS: 128 (59)

BR/BS: Élément 1 n = 218

biosimilaire LY-IGlar (BR/BS). Durée du suivi : Élément 1 : 52 semaines

Element-1

N.D.

N.D.

(-0,149 à 0,112) p > 0,05

Rosenstock (2015) 12 pays (Septembre 2011 à septembre 2012)


Inclusion : - Adultes (≥ 18 ans) - Diabète type 2 - Reçu ≥ 2 médicaments anti-

hyperglycémiques oraux à des doses stables depuis ≥ 12 semaines

- HbA1c ≥ 7,0 et ≤ 11,0% - IMC ≤ 45 kg/m2 Exclusion : - Usage de pramlintide, autres

insulines sauf IGlar (≤ 30 derniers jours), insuline glargine BS (≤ 90 derniers jours)

- Antécédents de traitement par bolus basal

Sous-population utilisant IGLAR avant l’étude

Sous-population utilisant IGLAR n = 299 BR/BS n = 155 BR/BR n = 144

Changement de traitement de Insuline IGLAR BR vers l’insuline LY-IGLAR BS selon la posologie recommandée. Durée du suivi : 28 semaines

Différence en HbA1c par rapport au niveau de base dans la moyenne des moindres carrés, % (± ET) : Dose basale quotidienne moyenne d’insuline, U/kg (± ET)

-1,01 (0,08)

0,53 (0,03)

-1,02 (0,08)

0,60 (0,03)

Différence : -0,004 (-0,193 à 0,185)

p > 0,05

p > 0,05

250

Auteur, (année),

pays (Période à

l’étude)


sites)




(n)



Résultats



(BR/BS)


Âge moyen ± ET BR/BR 60 ± 10 ans BR/BS 60 ± 9 ans Sexe Homme (% total): BR/BR : 68 (47 %) BR/BS : 73 (47 %)

BR : Biologique de référence; BS : Biosimilaire; ECRA : Essai contrôlé à randomisation aléatoire; ET : Écart type; HbA1c : Hémoglobine glyquée; IC : Intervalle de confiance; IMC : Indice de masse corporelle; N.D. : Non disponible.

251


Tableau E36 – Immunogénicité – Diabète

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)



Nombre total de

participants (n)



Résultats


Changement de

traitement (BR/BS)


INSULINE



Inclusion : - Adulte (18 à 65 ans) - Diagnostic de diabète de type 1 - Avoir suivi avec succès, 52 semaines de traitement à l'insuline glargine de référence dans l'étude INSTRIDE 1




- Autre médicament expérimental Âge moyen ± ET BR/BR 43,2 (12,7) BR/BS 44,8 (11,4) Homme (% total): BR/BR : 36 (57,1) BR/BS : 41 (64,1)



Nouveau AAM positif, n/total (% total)

9/63

(14,3 %)

9/64

(14,1 %)

p > 0,05

Hadjivianni (2016) Élément 1 : 9 pays Élément 2 : 12 pays (2001-2013)

Analyse post-hoc de 2 ECRA Élément 1 (52 sites) Élément 2 (62 sites)

Inclusion : Élément 1 : - Adultes (≥ 18 ans) - Diabète type 1 depuis ≥ 1 an - Insulinothérapie à bolus-basal

depuis ≥ 1 an - HbA1c ≤ 11,0 % - IMC ≤ 35 kg/m2. Élément 2 : - Adultes (≥ 18 ans)

n = 750 BR/BR : Élément 1 n = 234 Élément 2 n = 144

Les sujets ont été maintenus sur l’insuline IGlar BR (BR/BR) ou ont subi un changement de traitement et ont été traités avec le biosimilaire LY-IGlar (BR/BS).

n/total (% total) AAM positif Élément 1 Élément 2

23/234 (9,8 %)

4/144

(2,8 %)

27/218 (12,4 %)

9/155

(5,8 %)

p > 0,05

p > 0,05

252

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)



Nombre total de

participants (n)



Résultats


Changement de

traitement (BR/BS)


- Diabète type 2 - Reçu ≥ 2 médicaments anti-


- HbA1c ≥ 7,0 et ≤ 11,0% - IMC ≤ 45 kg/m2 Exclusion : Élément 1 : - Usage de IGlar BS, anti-




Élément-2 : - Usage de pramlintide, autres



Element-1 Âge moyen ± ET BR/BR 41 ± 13 ans BR/BS 41 ± 14 ans Sexe Homme (% total): BR/BR: 137 (59) BR/BS: 128 (59) Element-2 Âge moyen ± ET BR/BR 60 ± 10 ans

BR/BS: Élément 1 n = 218 Élément 2 n = 155

Durée du suivi : Élément 1 : 52 semaines Élément 2 : 28 semaines

Nouveau AAM positif Élément 1 Élément 2

9/234

(3,8 %)

N.D.

15/218 (6,8 %)

N.D.

p = 0,148

p > 0,05

253

Auteur, (année),

pays (Période à

l’étude)

Type d’étude

(Nombre de sites)



Nombre total de

participants (n)



Résultats


Changement de

traitement (BR/BS)


BR/BS 60 ± 9 ans Homme (% total): BR/BR : 68 (47) BR/BS : 73 (47)

AAM : Anticorps anti-médicament; BR : Biologique de référence; BS : Biosimilaire; ECRA : Essai comparatif à randomisation aléatoire; ET : Écart-type; HbA1c : Hémoglobine glyquée; IC : Intervalle de confiance; IMC : Indice de masse corporelle; N.D. : Non disponible

254

E.6.2 Innocuité

Tableau E37 – Innocuité – Diabète

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


INSULINE












n/total (% total) EIAT EIGAT EIAT causant l’arrêt du traitement

42/63 (66,7 %)

3/63

(4,8 %)

1/63 (1,6 %)

41/64 (64,1 %)

2/64

(3,1 %)

0/64 (0 %)

*p = 0,853

*p = 0,680

*p = 0,496

Hadjivianni (2016) Élément 1 : 9 pays Élément 2 : 12 pays (2001-2013)

Analyse post-hoc de 2 ECRA Élément 1 (52 sites) Élément 2 (62 sites)

Inclusion : Élément 1 : - Adultes (≥ 18 ans) - Diabète type 1 depuis ≥ 1 an - Insulinothérapie à bolus-

basal depuis ≥ 1 an - HbA1c ≤ 11,0 % - IMC ≤ 35 kg/m2. Élément 2 : - Adultes (≥ 18 ans)

n = 750 BR/BR : Élément 1 n = 234 Élément 2 n = 144

Les sujets ont été maintenus sur l’insuline IGlar BR (BR/BR) ou ont subi un changement de traitement et ont été traités avec le biosimilaire LY-IGlar (BR/BS). Durée du suivi : Élément 1 : 52 semaines

n/total (% total) EIAT Élément 1 Élément 2 EIAT-relié au traitement

144/234 (61,5 %)

69/144

(47,9 %)

136/218 (62,4 %)

75/155

(48,4 %)

p > 0,05

p > 0,05

255

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


- Diabète type 2 - Reçu ≥ 2 médicaments anti-


- HbA1c ≥ 7,0 et ≤ 11,0% - IMC ≤ 45 kg/m2 Exclusion : Élément 1 : - Usage de IGlar BS, anti-




Élément-2 : - Usage de pramlintide, autres



Element-1 Âge moyen ± ET BR/BR 41 ± 13 ans BR/BS 41 ± 14 ans Sexe Homme (% total): BR/BR: 137 (59) BR/BS: 128 (59) Element-2 Âge moyen ± ET BR/BR 60 ± 10 ans BR/BS 60 ± 9 ans

BR/BS: Élément 1 n = 218 Élément 2 n = 155

Élément 2 : 28 semaines Élément 1 Élément 2 EIGAT Élément 1 Élément 2

11/234 (4,7 %)

7/144

(4,9 %)

22/234 (9,4 %)

12/144 (8,3 %)

14/218 (6,4 %)

6/155

(3,9 %)

17/218 (7,8 %)

4/155

(2,6 %)

p > 0,05

p > 0,05

p > 0,05

p = 0,038

256

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


Homme (% total): BR/BR : 68 (47) BR/BS : 73 (47)

BR : Biologique de référence; BS : Biosimilaire; ECRA : Essai comparatif à randomisation aléatoire; EIAT : Effets indésirables apparus en cours de traitement; EIGAT : Effets indésirables graves apparus en cours de traitement; ET : Écart-type; HbA1c : Hémoglobine glyquée; IC : Intervalle de confiance * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

257

E.6.2 Rétention

Tableau E38 – Rétention – Diabète

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


INSULINE













58/63 (92,1 %)

61/64 (95,3 %)

p = 0,49

BR : Biologique de référence; BS : Biosimilaire; ECRA : Essai comparatif à randomisation aléatoire; ET : Écart-type; IC : Intervalle de confiance

258

E.7. Hématologie/Néphrologie


Tableau E39 – Perte d’efficacité – Hématologie/Néphrologie

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


ÉPOÉTINE α

Belleudi (2019) Italie (Janvier 2009 à décembre 2015)

Cohorte rétrospective (4 sites)

Inclusion : - Usage d’au moins un ESA α BR ou BS.

- ≥ 1 an d’assistance santé - Absence de prescription d'ESA au cours des 6 mois précédant les mesures de base

- Traités en raison d’un diagnostic de MRC

Exclusion : - Sujet n’ayant pas changé de traitements dans les 120 jours

Âge : Total : N.D. Sexe, Femme (% total): BR/BR: 48,0 % BR/BS + BR/autres: 8,4 % BS/BS : 51,1 % BS/BR + BS/Autres : 51,1 %

n = 4166 BR/BR: n = 1559 BR/BS: n = 221 BR/Autres: n = 1338 BS/BS: n = 524 BS/BR: n = 226 BS/autres: n = 298

Une portion des sujets avait été traitée avec l’ESA α BR et ensuite soit maintenue sur l’ESA α BR (BR/BR) ou traitée avec un l’ESA α BS (BR/BS) ou d’autres types d’ESA (BR/Autres). L’autre portion des sujets avait été traitée avec l’ESA α BS et ensuite soit maintenue sur l’ESA α BS (BS/BS) ou traitée avec l’ESA α BR (BS/BR) ou d’autres types d’ESA (BS/Autres). Outil d’évaluation : Transfusion sanguine, anémie. Durée du suivi : Maximum 1 an

Perte d’efficacité

N.D.

N.D.

BR/BR

vs BR/BS

RRIa : 0,86

(0,44 à 1,66) p = N.D.

BS/BS vs

BS/BR

RRIa : 1,38 (0,66 à 2,89)

p = N.D.

Haag-Weber (2009) Allemagne, Autriche (Période : N.D.)

ECRA, Double insu (56 sites)

Inclusion : - Adulte stable cliniquement - Anémique - Dialysé 3 fois/sem depuis ≥ 6 mois

- Hb entre 10-13 g/dl depuis ≥ 12 semaines

- Traité avec une dose stable d’ESA α, 3x semaine ≥ 8 semaines (dosage max : 300 IU/kg par semaine).

-

Semaine 0 à 28 : n = 478 BR/BR n = 164 BS/BS n = 314 Population ITT n = 465

Les sujets ont soit été maintenus sur l’ESA α BR (BR/BR) ou traités avec un l’ESA α BS (HX575) (BR/BS). Outil d’évaluation : Concentration de Hb Réponse au traitement Sujets avec une valeur moyenne d'Hb pendant la

Changement dans la concentration d’Hb : Moyenne des moindres carrés (IU/semaine ± ET) de la moyenne absolue de changement dans la concentration de Hb Population PP

0,063 ± 0,117

0,147 ± 0,092

0,084 (-0,170 à

0,338)

259

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


Exclusion : - Transfusion de globules rouges depuis < 14 semaines

- Condition pouvant affecter l’érythropoïéthèse (p.ex. : condition hématologique, hépatique, immunologique, infectieuse)

- Prise antérieure d’agents immunosuppréseurs (1 mois) ou d’androgène (2 mois)

Âge moyen (écart) : BR/BR: 62,6 (24-88) ans BR/BS: 62,3 (23-90) ans Sexe, Femme (% total) : BR/BR: 66 (40,2 %) BR/BS: 138 (43,9 %)

BR/BR n = 161 BR/BS: n = 304 Population PP n = 325 BR/BR: n = 118 BR/BS: n = 207

période de maintenance et d'évaluation se situant entre 10,0 et 13,0 g/dl. Durée de suivi : 28 semaines

Population ITT Sujets (Population PP) ayant répondus au traitement, n/total (% total) (IC à 95 %)

-0,187 ± 0,105

96/118 (81,4 %)

(73,1 à 87,9)

0,003 ± 0,079

167/207 (80,7 %)

(74,6 à 85,8)

0,189 (-0,039 à

0,418)

*p = 1,000

Minutolo (2017) Italie (Janvier 2011 à octobre 2014)


Inclusion : - Adulte stable cliniquement - Traité avec ESA BR. Exclusion : - Saignement ou transfusion moins de 6 mois avant le changement de traitement

- Dose d’ESA α BR > 1000 IU/sem, 3 mois avant le changement de traitement.

Âge moyen ± ET : BR/BR: 69,3 ± 12,8 ans BR/BS: 70,1 ± 13,3 ans Sexe, Femme (% total): BR/BR: 61 (37,4 %) BR/BS: 61 (37,4 %)

n = 326 BR/BR: n = 163 (Epoetin α: 77; Epoetin ß: 59; Darbepoetin: 27) BR/BS: n = 163 (HX575: 125 SB309: 38)

Les sujets ont soit été maintenus sur une ESA BR (BR/BR) ou traités avec une ESA BS (BR/BS). Outil d’évaluation : Concentration de Hb calibrée par le temps d’observation (TWAHb) Hyporéactivité : Deux augmentations de dose d'ESA au-delà de 50 % de la dose à laquelle une concentration d'Hb stable avait été obtenue chez le sujet Durée du suivi : 24 semaines

TWAHb (g/dl) Incidence cumulatif d’hyporéactivité à l’ESA, %

11,24 ± 0,56

18,4 %

11,04 ± 0,69

41,1 %

Différence : -0,20

(-0,33 à -0,06) p < 0,001

p < 0,001

Thadhani (2018) États-Unis

ECRA ouvert (46 sites)

Inclusion : - Adulte (≥ 18 ans) - Anémique et atteint de MRC - Traité de façon régulière avec Epogen®

n = 432 BR/BR: 206 BR/BS: 212

Les sujets ont soit été maintenus sur l’Epogen® (BR/BR) ou traités avec RetacritTM (epoetin zeta)

Proportion de temps pendant laquelle les patients avaient des concentrations de Hb dans la plage cible

.

260

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


(Juillet 2015 à janvier 2016)

- Utilisation de l’algorithme de dosage : IV Epogen® version FMCNA ESA

Exclusion : - Femme enceinte ou en allaitement

- Femme fertile sans moyen de contraception efficace

- Transfusion de produits sanguins : o 1 au cours des 3 derniers

mois, o ≥ 2 au cours de la dernière

année - Don ou perte de sang (> 475 ml) dans les 3 derniers mois

- Utilisation d’ESA à longue durée d’action dans les 16 dernières semaines

Âge moyen ± ET : BR/BR: 59,3 ± 14,23 ans BR/BS: 60,5 ± 13,96 ans Sexe, Femme (% total) : BR/BR: 102 (49,5 %) BR/BS: 82 (38,7 %)

Population PP n = 267 BR/BR: 130 BR/BS: 137

(BR/BS) tous deux administrés par IV. Plage cible (concentration de Hb) : 9 à 11 g/dL Outil d’évaluation : Proportion de temps pendant laquelle les sujets avaient des concentrations de Hb dans la plage cible au cours des 8 dernières semaines de l'étude. Calcul de la proportion de temps : Nombre de mesures de taux de Hb dans la plage cible divisé par le nombre total de mesures de Hb effectuées. Durée du suivi : 24 semaines

Population FAS Moyenne (%) ± ET Proportion estimée, % (IC à 95 %) Population PP Proportion estimée, % (IC à 95 %)

62,8 ± 30,8 %

63,3 % (58,7 à 67,7)

N.D.

62,6 ± 30,2 %

61,9 % (57,5 à 66,2)

N.D.

p = N.D.

Différence estimée : -1,4

(-7,6 à 4,9)

Différence estimée : -4,3 (-11,4 à 2,8)

BR: Biologique de référence; BS: Biosimilaire; ECRA : Essai contrôlé à randomisation aléatoire; ESA : Erythropoiesis-stimulating agent; ET, Écart-type; FAS : Full analysis set; FMCNA : Fresenius Medical Care North America; Hb : Hémoglobine; IC : Intervalle de confiance; ITT : Intention de traiter; IU : International unit; IV : Intraveineuse; MRC: Maladie rénale chronique; N.D. : Non-disponible; PP : Per-protocol; RRIa : Rapport de risque instantané ajusté (Hazard ratio); SD : Déviation standard; TWA : Time-weighted average * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php)

261


Tableau E40 – Immunogénicité – Hématologie/Néphrologie

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


ÉPOÉTINE α










Semaine 0 à 28 : n = 478 BR/BR n = 164 BS/BS n = 314 Population ITT n = 465 BR/BR n = 161 BR/BS: n = 304 Population PP n = 325 BR/BR: n = 118 BR/BS: n = 207

Les sujets ont soit été maintenus sur l’ESA α BR (BR/BR) ou traités avec un l’ESA α BS (HX575) (BR/BS). Durée de suivi : 28 semaines

n/total (% total) AAMN positif

0/164 (0 %)

0/314 (0 %)

S.O.

AAMN, anticorps anti-médicament neutralisant; BR: Biologique de référence; BS: Biosimilaire; ECRA : Essai contrôlé à randomisation aléatoire; ESA : Erythropoiesis-stimulating agent; Hb : Hémoglobine; IC : Intervalle de confiance; ITT : Intention de traiter; PP : Per-protocol; S.O. : Sans objet

262

E.7.3 Innocuité

Tableau E41 – Innocuité – Hématologie/Néphrologie

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


ÉPOÉTINE α

Belleudi (2019) Italie (Janvier 2009 à décembre 2015)


Inclusion : - Usage d’au moins un ESA α BR ou BS.

- ≥ 1 an d’assistance santé - Absence de prescription d'ESA au cours des 6 mois précédant les mesures de base

- Traités en raison d’un diagnostic de MRC

Exclusion : - Sujet n’ayant pas changé de traitements dans les 120 jours

Âge : Total : N.D. Sexe, Femme (% total): BR/BR: 48,0 % BR/BS + BR/autres: 8,4 % BS/BS : 51,1 % BS/BR + BS/Autres : 51,1 %

n = 4166 BR/BR: n = 1559 BR/BS: n = 221 BR/Autres: n = 1338 BS/BS: n = 524 BS/BR: n = 226 BS/autres: n = 298

Une portion des sujets avait été traitée avec l’ESA α BR et ensuite soit maintenue sur l’ESA α BR (BR/BR) ou traitée avec un l’ESA α BS (BR/BS) ou d’autres types d’ESA (BR/Autres). L’autre portion des sujets avait été traitée avec l’ESA α BS et ensuite soit maintenue sur l’ESA α BS (BS/BS) ou traitée avec l’ESA α BR (BS/BR) ou d’autres types d’ESA (BS/Autres). Outil d’évaluation : Transfusion sanguine, anémie. Durée du suivi : Maximum 1 an

EI

N.D.

N.D.

BR/BR

vs BR/BS

RRIa : 1,18

(0,49 à 2,83) p = N.D.

BS/BS

vs BS/BR

RRIa : 1,52

(0,54 à 3,90) p = N.D.

Thadhani (2018) États-Unis (Juillet 2015 à janvier 2016)






- Transfusion de produits sanguins :

n = 432 BR/BR: 206 BR/BS: 212 Population PP n = 267 BR/BR: 130 BR/BS: 137

Les sujets ont soit été maintenus sur l’Epogen® (BR/BR) ou traités avec RetacritTM (epoetin zeta) (BR/BS) tous deux administrés par IV. Durée du suivi : 24 semaines

n/total (% total) EIAT EIAT-reliés au médicament EIGAT EIGAT-reliés au médicament

122/206 (59,2 %)

1/206

(0,5 %)

32/206 (15,5 %)

0/206 (0 %)

9/206

135/212 (63,7 %)

3/212

(1,4 %)

34/212 (16,0 %)

1/212

(0,5 %)

13/212

*p = 0,367

*p = 0,623

*p = 0,894

*p = 1,000

*p = 0,656

263

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


o 1 au cours des 3 derniers mois,

o ≥ 2 au cours de la dernière année

- Don ou perte de sang (> 475 ml) dans les 3 derniers mois



EIAT causant l’arrêt du traitement**

(4,4 %)

(6,1 %)

BR: Biologique de référence; BS: Biosimilaire; ECRA : Essai contrôlé à randomisation aléatoire; EI : Effets indésirables; EIAT : Effets indésirables apparus en cour de traitement; EIGAT : Effets indésirables graves apparus en cour de traitement; ESA : Erythropoiesis-stimulating agent; ET : Écart-type; FMCNA : Fresenius Medical Care North America; Hb : Hémoglobine; IC : Intervalle de confiance; IV : Intraveineuse; MACE : Major adverse cardiovascular events; MRC: Maladie rénale chronique; N.D. : Non-disponible; PP : Per-protocol; RRIa : Rapport de risque instantané ajusté (Hazard ratio); * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php) ** Valeurs tirées du tableau 3, toutefois ces valeurs diffèrent de celles présentes dans la figure 1, mais la différence demeure non statistiquement significative.

264

E.7.4 Rétention

Tableau E42 – Rétention – Hématologie/Néphrologie

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)


ÉPOÉTINE α










Semaine 0 à 28 : n = 478 BR/BR n = 164 BS/BS n = 314 Population ITT n = 465 BR/BR n = 161 BR/BS: n = 304 Population PP n = 325 BR/BR: n = 118 BR/BS: n = 207

Les sujets ont soit été maintenus sur l’ESA α BR (BR/BR) ou traités avec un l’ESA α BS (HX575) (BR/BS). Durée de suivi : 28 semaines

n/total (% total) Taux de rétention

142/164 (86,6 %)

261/314 (83, 1 %)

*p = 0,356

Thadhani (2018) États-Unis (Juillet 2015 à janvier 2016)




n = 432 BR/BR: 206 BR/BS: 212 Population PP n = 267

Les sujets ont soit été maintenus sur l’Epogen® (BR/BR) ou traités avec RetacritTM (epoetin zeta) (BR/BS) tous deux administrés par IV. Durée du suivi : 24 semaines

n/total (% total) Taux de rétention Raison (n/total arrêté) : - EI** - Critère de retrait

158/206 (76,7 %)

12/48 26/48

156/212 (73,6 %)

15/56 27/56

*p = 0,498

S.O. S.O.

265

Auteur, (année),

pays (Période à

l’étude)


sites)



Nombre total de

participants (n)



Résultats



(BR/BS)




- Transfusion de produits sanguins : o 1 au cours des 3 derniers

mois, o ≥ 2 au cours de la dernière

année - Don ou perte de sang (> 475 ml) dans les 3 derniers mois



BR/BR: 130 BR/BS: 137

- Perdu au suivi - Décision de l’investigateur - Retrait par le patient

7/48 2/48 1/48

6/56 1/56 7/56

S.O. S.O. S.O.

BR: Biologique de référence; BS: Biosimilaire; ECRA : Essai contrôlé à randomisation aléatoire; EI : Effets indésirables; ESA : Erythropoiesis-stimulating agent; ET : Écart-type; FMCNA : Fresenius Medical Care North America; Hb : Hémoglobine; IC : Intervalle de confiance; ITT : Intention de traiter; IV : Intraveineuse; MRC: Maladie rénale chronique; N.D. : Non-disponible; PP : Per-protocol; S.O. : Sans objet * Test exact de Fisher, calculé par l’INESSS avec Medcal® software (https://www.medcalc.org/calc/odds_ratio.php); ITT : Intention de traiter; ** Valeurs tirées de la figure 1, toutefois ces valeurs diffèrent dans le tableau 3.

266

E.8. Effets indésirables – Études sans comparateur

Tableau E43 – Effets indésirables – Changement de traitement d’un BR vers un BS - Études sans comparateur

Auteur (année) Changement de

traitement : BR →BS

Participants; (Durée du suivi)

Pathologie EI ou EIAT (% total)

EIG ou EIGAT (% total)

Description EIG/EIGAT Arrêt de traitement

lié aux EI/EIAT

Abdalla (2017)

Infliximab → CT-P13

n = 34 (15,8 mois)

PR, SA, AP 58,8 % 8,8 %

- Cancer - Réactivation de tuberclose - Infection respiratoire ou urinaire

- Gastroentérite - Infection occulaire - Infection des oreilles

2,9 %

Argüelles-Arias (2017)


n = 98; (12 mois)

MII (MC, CU)

11,2 % 2,0 % - Syndrome de Sweet - Paresthésie

6,1 %

Avouac (2018)


n = 260 (variable)

Multiple (PR, SA, MC, CU)

N.D. N.D. - N.D. 1,9 %

Benucci (2017)


n = 41 (6 mois)

SA N.D. N.D. - Psoriasis palmoplantaire 3,0 %

Bergqvist (2018)


n = 313 (12 mois)

MC (n = 195)

24,1 % 2,1 %

- Psoriasis - Lupus érythémateux

systémique - Leucémie myéloïde

chronique - Mélanome - Purpura de Henoch-

Schönlein - Pustulose palmoplantaire

7,2 %

CU (n = 118)

21,2 % 2,5 % 0,8 %

Bonifati (2019)

Etanercept → SB4

n = 87 (12 mois)

AP N.D. N.D. - Fibrose pulmonaire - AVC - Éruption cutanée

3,4 %

Bronswijk (2020)


n = 361 (6 mois)

MII (MC, CU)

2,2 % N.D. - N.D. N.D.

Buer (2017)


n = 143 (6 mois)

MC (n = 99)

14,1 %

N.D. - N.D.

1,0 %

CU (n = 44)

6,8 % 2,3 %

Cohen (2020)

Infliximab → PF-06438179/GP1111

n = 126 (24 semaines)

PR 30,2 % 2,4 % - N.D. 1,6 %

Eberl (2017)


n = 62 (variable)

MII (MC, CU, MIInc)

4,8 % N.D. - N.D. 0 %

Emery (2017)

Etanercept → SB4


PR 48,7 % 1,7 % - Infection sérieuse 1,7 %

267







lié aux EI/EIAT

Fabiani (2019)

TNF-α Inhibiteurs → BS

n = 37 (62 yeux) (variable)

Uvéite 5,4 % 0 % - N.D. N.D.

Felis-Giemza (2019)

etanercept → SB4

n = 162 (3 à 6 mois)

PR, SR, AP N.D. N.D. - N.D. 8,0 %

Gervais (2018)


n = 33 (12 mois)

MII (MC, CU, MIInc)

N.D. N.D. - N.D. 0 %

Glintborg (2017) Infliximab →

CT-P13 n = 802

(413 jours) PR, SA, AP N.D. N.D. - N.D. 4,6 %

Glintborg (2019) Etanercept →

SB4 n = 1621

(383 jours) PR, SA, AP N.D. N.D. - N.D. 4,8 %

Goll (2019)



Multiple (PR, SA, AP, Ps,

MC, CU) 40 % 4 %

- Troubles cardiaques - Problèmes gastro-intestinaux - Troubles généraux et

anomalies au site d'administration

- Infections et infestations - Troubles rénaux et urinaires

0,5 %

Guerra Veloz (2018) REED


n = 167 (12 mois)

MII (MC, CU)

7,2 % 1,8 % - Syndrome de Sweet - Paresthésie - Méningiome

4,2 %

Guerra Veloz (2019)


n = 100 (24 mois)

MII (MC, CU)

14,0 % N.D. - Accident cérébrovasculaire - Syndrome de Sweet - Paresthésie

4,0 %

Guerrero Puente (2017)


n = 36 (Variable)

MC (n = 23)

13,0 % 4,3 %

- Pneumonie

4,3 %

CU (n = 13)

0 % 0 % 0 %

Guiotto (2019)


n = 53 (24 mois)

MII (MC, CU)

7,5 % N.D. - N.D. N.D.

Hoivik (2018)


n = 143 (18 mois)

MII (MC, CU)

51,7 % 3,5 %

- Lymphome à cellules B

- Crampes et vomissements - Étourdissements aigus - Attaque ischémique

transitoire - Maux d'estomac

2,1 %

Jaworski (2019)

Etanercept → SDZ ETN

n= 166 (48 semaines)

PR 25,3 % N.D. - N.D. 2,4 %

Kolar (2017)



MII (MC, CU)

N.D. N.D. - Arthralgie grave - Dysplasie fibreuse maxillaire

2,7 %

Matsuno (2019)

Infliximab → NI-071


PR 57,5 %

(29,4 %)¥ 3,9 %

(2,9 %)¥¥

- Pneumonie - Leucémie aigue - Diabetes mellitus

7,8 %

268







lié aux EI/EIAT

Nikiphorou (2015)


n = 39 (24 mois)

PR, SA, AP, AJ, AR N.D. 5,1 % - Tuberculose - Neurofibromatose

5,1 %

Park (2017)

Rituximab → CT-P10


PR 20,0 % 5,0 % (0 %)¥¥

- Ostéoarthrite spinale 0 %

Park (2017)


n = 84 (48 mois)

SA 71,4 %

(39,3 %)¥ 4.8 %

(1,2 %)¥¥

- Tuberculose - Cellulite - Cancer de la prostate

4,8 %

Pescitelli (2019)

Etanercept → SB4


PR, Ps 12,5 % N.D. - N.D. N.D.

Petitdidier (2019)


n = 113 (12 mois)

MII (MC, CU, MIInc)

18,0 % 1,8 % - N.D. N.D.

Plevris (2019)


n = 110 (12 mois)

MC 53,8 PYD 13,5 PYD - Infections - Paresthésie - Méningite lymphotique

6,4 %

Razanskaite (2017)


n= 143 (Variable)

MII (MC, CU, MIInc)

N.D. N.D. - N.D. 9.1%

Scherlinger (2018)



PR, SA 10,1 % N.D. - N.D. 1,1 %

Schmitz (2017)

Infliximab → INB

n = 27 (12 mois)

PR, AP, SA, Ps, N.D. N.D. - N.D. 7,4 %

Schmitz (2018)


n = 133 (± 12 mois)

MII (MC, CU)

N.D. N.D. - N.D. 9,8 %

Sieczkowska (2016)


n = 39 (Variable)

MC (n= 32)

N.D. N.D. - Tératome ovarien - Varicelle/zona

3,1 %

CU (n = 7)

14,3 %

Smits (2016)



MII (MC, CU, MIInc)

28,9 % (7,2 %)¥

0 % - N.A. 2,4 %

Smits (2017)



MII (MC, CU, MIInc)

47,0 % 3,6 %

- Obstruction intestinale - Torsion rétrostomale - Adhérences intra-

abdominales

7,2 %

Smits (2019)



MII (MC, CU, MIInc)

Semaine 52 à 104 :

27,9 %

Semaine 52 à 104 :

4,4 %

Semaine 52 à 104 : - Proctite ulcéreuse - Pyélonéphrite - Urolithiase

8,4 %

269







lié aux EI/EIAT

Strik (2018)



MC (n = 60)

76,7 % (30,0 %)¥

5,0 % (1,7 %)¥¥

- Abcès périanaux - Métastase - Lymph-adénopathie - Syndrome du tunnel carpien

0 % CU

(n = 58) 82,8 %

(36,2 %)¥ 5,2 % (0 %)¥¥

Tanaka (2016)



PR 87,9 % 12,1 %

- Entérocolite - Rupture tendineuse - Cancer du colon - Maladie pulmonaire

interstitielle

24,2 %

Tweehuysen (2018) Infliximab →

CT-P13 n = 192 (6 mois)

PR, SA, AP 73,4 % 4,7 % - Évènement cardiovasculaire

ou pulmonaire - Cancer

32,4 %

Yoo (2017)



PR 53,8 %

(18,9 %)¥ 9,1 %

(2,8 %)¥¥

- Cancer du sein - Cancer ovarien - Lymphome - Salpingite

5,6 %

AJ, arthrite juvénile; AP, Arthrite psoriasique; AR, arthrite réactionnelle; BR : Biologique de référence; BS : Biosimilaire; CU : Colite ulcéreuse; DT2, diabète de type 2; EI, effets indésirables; EIAT : Effets indésirables apparus en cours de traitement; EIG : Effets indésirables graves; EIGAT : Effets indésirables grave apparus en cours de traitement; MC : Maladie de Crohn; MII : Maladie inflammatoire de l'intestin;

MIInc : MII non-classée; N.A. : Non applicable; N.D., non disponible; PR, polyarthrite rhumatoïde; Ps : psoriasis en plaques; PYD : Patient-years of follow-up; SA, spondyloarthrite ankylosante; ¥ EIAT-reliés au médicament ¥¥ EIGAT-reliés au médicament

270

ANNEXE F

Appréciation de la preuve scientifique

Tableau F1 – Critères d’appréciation de la qualité de la preuve scientifique

Critères d’appréciation Échelles d’appréciation

Qualité méthodologique des études

• La quantité d’études incluses dans la synthèse de données

• Le plan d’étude optimal pour répondre à la question d’évaluation

• Le risque de biais/respect des critères méthodologiques.

• La précision (taille de l’échantillon optimale et puissance statistique)

Qualité très élevée ✓ Au moins une étude ou une synthèse d’études dont les plans sont appropriés

pour répondre à la question d’évaluation ou de pratique, de bonne qualité méthodologique avec un faible risque de bais. OU

✓ Plusieurs études ou une synthèse d’études dont les plans sont suffisamment appropriés pour répondre à la question d’évaluation ou de pratique, de bonne qualité méthodologique avec un faible risque de bais.

Qualité élevée ✓ Une ou deux études dont les plans sont suffisamment appropriés pour

répondre à la question d’évaluation ou de pratique, de bonne qualité méthodologique avec un faible risque de biais.

✓ Une synthèse d'études dont les plans sont peu appropriés pour la question d’évaluation ou clinique, de bonne qualité méthodologique avec un faible risque de biais.

Qualité modérée ✓ Plusieurs études ou une synthèse d'études dont les plans sont appropriés à la

question d’évaluation ou de pratique, de moyenne qualité méthodologique avec un risque modéré de biais.

✓ Une ou deux études dont les plans sont peu appropriés à la question d’évaluation ou de pratique, de bonne qualité méthodologique avec un risque modéré de biais.

Qualité faible ✓ Plusieurs études ou une synthèse d’études dont les plans sont appropriés à la

question d’évaluation ou de pratique, de faible qualité méthodologique avec un risque majeur de biais.

✓ Plusieurs études ou une synthèse d’études dont les plans sont suffisamment appropriés à la question d’évaluation ou de pratique, de faible qualité. méthodologique avec un risque majeur de biais.

✓ Au moins une étude ou synthèse d’études dont les plans sont peu appropriés à la question d’évaluation ou de pratique, de faible qualité méthodologique avec un risque majeur de biais.

271

Critères d’appréciation Échelles d’appréciation

Cohérence / Fiabilité

• La cohérence dans l’effet de l’intervention, en considérant la comparabilité des populations, des méthodes et des outils de mesure

• La complémentarité et la diversité des méthodes et des mesures

Cohérence très élevée ✓ Toutes les études sont cohérentes.

Cohérence élevée ✓ La plupart des études sont cohérentes et l’incohérence peut être expliquée.

Cohérence modérée ✓ L’incohérence reflète une véritable incertitude autour de la question clinique.

Cohérence faible ✓ Les études sont incohérentes.

Non applicable (1 seule étude)

Impact clinique ou organisationnel

• L’importance clinique/organisationnelle/sociale de l’effet

• L’atteinte des objectifs d’intervention

Impact très élevé ✓ L’impact clinique des résultats est très grand.

Impact élevé ✓ L’impact clinique des résultats est substantiel ou important.

Impact modéré ✓ L’impact clinique des résultats est modéré.

Impact faible ✓ L’impact clinique des résultats est limité ou insuffisant.

La généralisabilité / transférabilité

• La similarité entre les populations et les contextes à l’étude et ceux ciblés

• La possibilité d’adaptation de l’intervention

Généralisabilité/transférabilité très élevée ✓ La population étudiée est la même que la population ciblée. Par conséquent,

les résultats rapportés dans la littérature sont généralisables à la population cible.

Généralisabilité/transférabilité élevée ✓ La population étudiée est similaire à la population ciblée. Par conséquent, les

résultats rapportés dans la littérature sont généralisables à la population cible avec quelques mises en garde.

Généralisabilité/transférabilité modérée ✓ La population étudiée diffère de la population ciblée. Par conséquent, les

résultats rapportés dans la littérature ne sont pas directement généralisables à la population cible, mais pourraient être appliqués de façon judicieuse à la population ciblée.

Généralisabilité/transférabilité faible ✓ La population étudiée diffère de la population ciblée. Par conséquent, les

résultats rapportés dans la littérature ne sont pas directement généralisables à la population cible et il est difficile de juger s’il est judicieux de les appliquer à la population ciblée.

272

Tableau F2 – Appréciation de la preuve pour la Gastroentérologie

Question de recherche : Est-ce que la substitution d'un médicament biologique pour un autre (référence ou biosimilaire) augmente le risque de perte d’efficacité, d’innocuité

Population : Personnes sous traitement par un médicament biologique atteint de MII (maladie de Crohn, colite ulcéreuse ou MII non définie) Intervention : Transfert d’un médicament biologique de référence vers un médicament biosimilaire (ou vice versa) ou de deux médicaments biosimilaires entre eux. Comparaison : Aucun transfert (maintien du traitement)

Paramètres de résultat

Transfert : BR vers BS ou BS vers BR

Nb patients (nb études)

Appréciation de la qualité de la preuve Niveau de preuve

Critères Appréciation Commentaires


Aucune différence statistiquement significative

n = 1 053 (2 ECRA; 2 cohortes prospectives et 3 cohortes rétrospectives)

Qualité méthodologique

Faible

Quantité d’études : 7 études Plan d’étude : ECRA, Cohorte, ECRA Jorgensen (6 indications) Risque de biais : Moyen; Des risques biais sont présents (surtout pour les cohortes) : taille des groupes variable, absence critère de sélection, devis ouvert, durée étude différente et co-médication différente Précision : Faible (analyse statistique adéquate généralement présente; manque de puissance)

Faible Cohérence Très élevée Toutes les études sont cohérentes. Aucune des différences obtenues n’est statistiquement significative.

Impact clinique de l’intervention

Élevée L’objectif de l’intervention était de démontré une similarité entre les 2 traitements. L’impact clinique est similaire.

Généralisabilité Modérée

Études réalisées sur des populations européenne et asiatique dans plusieurs établissements pour les ECRA (un total de 83 établissements). Pour les cohortes, les études ont été réalisées en République de Corée, en République Tchèque, en Espagne, en Belgique et au Royaume-Uni, chacun dans un seul établissement. Deux cohortes réalisées avec une population pédiatrique.

Immunogénicité

• Présence d’AAM et AAMN


n = 480 (1 ECRA, 1 cohorte prospective, 1 cohorte rétrospective) n = 482 (ECRA Jorgensen)


Faible

Quantité d’études : 4 études Plan d’étude : ECRA, cohorte, ECRA Jorgensen (6 indications) Risque de biais : Faible; Des risques biais sont présents (surtout pour les cohortes) : devis ouvert, sans randomisation, co-médication différente. Précision : Modérée

Faible

Cohérence Modéré

Trois études sur 4 sont cohérentes, avec aucune différence statistiquement significative. Une étude (ECRA) est statistiquement significative en faveur du BR quant à la présence de nouveaux sujet AAM positif.



Généralisabilité Faible

Études réalisées sur des populations européenne et asiatique dans plusieurs établissements pour l’ECRA (58 établissements) pour la MC seulement. Cohorte rétrospective réalisée en République Tchèque et cohorte prospectiveréalisée en République de Corée dans un seul établissement avec une population pédiatrique.

Apparition d’effets indésirables

n = 742 Qualité méthodologique

Modérée Quantité d’études : 6 études Plan d’étude : ECRA, cohorte, ECRA Jorgensen (6 indications)

Modérée

273







(1 ECRA, 2 cohortes prospectives et 2 cohortes rétrospectives) n = 482 (ECRA Jorgensen)

Risque de biais : Moyen; des risques biais sont présents (surtout pour les cohortes) : taille des groupes variable, absence critère de sélection, devis ouvert, durée de suivi différent, co-médication différente. Précision : faible (peu d’analyses statistiques et de calcul de puissance

Cohérence Très élevée Toutes les études sont cohérentes. Aucune des différences obtenues n’est statistiquement significative.




Études réalisées sur des populations européenne et asiatique dans plusieurs établissements pour l’ECRA (58 établissements) pour la MC seulement. Pour les cohortes, les études ont été réalisées en République de Corée, en Espagne, en belgique et au Royaume-Uni, chacun dans un seul établissement. Deux cohortes réalisées avec une population pédiatrique.

Apparition d’effets indésirables graves


n = 532 (1 ECRA, 1 cohorte prospective et 2 cohortes rétrospectives) n = 482 (ECRA Jorgensen)


Faible

Quantité d’études : 5 études Plan d’étude : ECRA, cohorte, ECRA Jorgensen (6 indications) Risque de biais : Moyen; des risques biais sont présents (surtout pour les cohortes) : taille des groupes variable, absence critère de sélection, devis ouvert, durée de suivi différent, co-médication différente. Précision : faible (peu d’analyses statistiques et de calcul de puissance

Modérée Cohérence Très élevée Toutes les études sont cohérentes. Aucune des différences obtenues n’est statistiquement significative.




Études réalisées sur des populations européenne et asiatique dans plusieurs établissements pour l’ECRA (58 établissements) pour la MC seulement. Pour les cohortes, les études ont été réalisées en République de Corée, en Espagne et en Belgique, chacun dans un seul établissement. Deux cohortes réalisées avec une population pédiatrique.

Taux de rétention Aucune différence statistiquement significative

n = 490 (1 ECRA, 1 cohorte prospective et 1 cohorte rétrospective) n = 482 (ECRA Jorgensen)


Faible

Quantité d’études : 4 études Plan d’étude : ECRA, cohorte, ECRA Jorgensen (6 indications) Risque de biais : Moyen; des risques biais sont présents (surtout pour les cohortes) : taille des groupes variable, absence critère de sélection, devis ouvert, durée de suivi différent, co-médication différente. Précision : faible (peu d’analyses statistiques et de calcul de puissance

Modéré




274







Études réalisées sur des populations européenne et asiatique dans plusieurs établissements pour l’ECRA (58 établissements) pour la MC seulement. Pour les cohortes, les études ont été réalisées en République de Corée et en Espagne, chacun dans un seul établissement. Une des cohortes a été réalisées avec une population pédiatrique.

275

Tableau F3 – Appréciation de la preuve pour la Rhumatologie


Population : Personnes sous traitement par un médicament biologique atteint d’arthrite inflammatoire (polyarthrite rhumatoïde, spondylarthrite ankylosante ou arthrite psoriasique) Intervention : Transfert d’un médicament biologique de référence vers un médicament biosimilaire (ou vice versa) ou de deux médicaments biosimilaires entre eux. Comparaison : Aucun transfert (maintien du traitement)








n = 7 098 (6 ECRA; 3 cohortes prospectives et 2 cohortes rétrospectives)


Élevée

Quantité d’études : 11 études Plan d’étude : ECRA, cohorte, ECRNA comparé à cohorte historique Risque de biais : Moyen; Des risques biais sont présents (surtout pour les cohortes : taille des groupes variable, absence critère de sélection, durée du suivi différente, co-médication différente. Précision : Modérée (analyse statistique adéquate généralement présente; puissance faible par indication)

Élevé Cohérence Élevée

Dix études sur 11 sont cohérentes avec aucune différence statistiquement significative. Une étude est statistiquement significative en faveur du BR pour PR et AP, mais est statistiquement significative en faveur du BS pour la SA.



Généralisabilité Élevée

Études réalisées sur des populations en Europe et aux États-Unis dans plusieurs établissements pour les ECRA (un total de 524 établissements). Pour les cohortes, les études ont été réalisées au Danemark, en Espagne, en Grèce et aux Pays-Bas. La majorité des participants étaient atteints de PR.

Immunogénicité



n = 3 431 (7 ECRA) n = 482 (ECRA Jorgensen)


Élevée

Quantité d’études : 8 études Plan d’étude : ECRA, ECRA Jorgensen (6 indications) Risque de biais : Faible; sélection variable, co-médication différente, absence critère de sélection. Précision : Modérée (analyse statistique adéquate, manque de puissance pour extension)

Modéré Cohérence Très élevée

Toutes les études sont cohérentes. Aucune des différences obtenues n’est statistiquement significative.



Généralisabilité Modérée Études réalisées sur des populations Europe et aux États-Unis dans plusieurs établissements pour les ECRA (673 établissements). Tous les participants étaient atteints de PR.



n = 4 584 (7 ECRA, 2 cohortes prospectives) n = 482


Modérée

Quantité d’études : 10 études Plan d’étude : ECRA, cohorte, ECRA Jorgensen (6 indications) Risque de biais : Moyen; des risques biais sont présents (surtout pour les cohortes) taille des groupes variable, absence critère de sélection, devis ouvert, durée du suivi différente, co-médication différente.

Modérée

276






(ECRA Jorgensen)

Précision : faible (peu d’analyses statistiques et de calcul de puissance)

Cohérence Élevée Neuf études sur 10 sont cohérentes avec aucune différence statistiquement significative. Une étude est statistiquement significative en faveur du BR.




Études réalisées sur des populations Europe et aux États-Unis dans plusieurs établissements pour les ECRA (681 établissements). Pour les cohortes, les études ont été réalisées en en Espagne et aux Pays-Bas, chacune dans un seul établissement. La majorité des participants étaient atteints de PR.



n = 3 447 (7 ECRA, 2 cohortes prospectives) n = 482 (ECRA Jorgensen)


Modérée

Quantité d’études : 10 études Plan d’étude : ECRA, cohortes, ECRA Jorgensen (6 indications) Risque de biais : Faible; peu de risques de biais sont présents (surtout pour le cohotres) : taille des groupes variable, absence critère de sélection, devis ouvert, durée du suivi différente, co-médication différente. Précision : Faible (peu d’analyses statistiques et de calcul de puissance)






Études réalisées sur des populations Europe et aux États-Unis dans plusieurs établissements pour les ECRA (681 établissements). Les cohortes ont été réalisées en Espagne et en Grèce dans un seul établissement. La majorité des participants étaient atteints de PR.

Taux de rétention


n = 7 932 (5 ECRA, 5 cohortes prospectives, 3 cohortes rétrospectives) n = 482 (ECRA Jorgensen)


Modérée

Quantité d’études : 13 études Plan d’étude : ECRA, cohortes, ECRNA comparé à cohorte historique, ECRA Jorgensen (6 indications) Risque de biais : Moyen; des risques biais sont présents (surtout pour les cohortes) : taille des groupes variable, absence critère de sélection, devis ouvert, durée du suivi différente et co-médication différente. Précision : faible (peu d’analyses statistiques et de calcul de puissance) Modérée

Cohérence Élevée

Neuf études sur 13 sont cohérentes avec aucune différence statistiquement significative. Trois études (cohortes) montrent un taux de rétention statistiquement significatif plus élevé pour le groupe BR alors qu’une ECRNA montre un taux de rétention statistiquement significatif plus élevé pour le groupe BS.



277







Études réalisées sur des populations Europe et aux États-Unis dans plusieurs établissements pour les ECRA (449 établissements). Pour les cohortes, les études ont été réalisées au Danemark, en Grèce, en France, aux Pays-Bas, en Espagne et en Turquie. La majorité des participants étaient atteints de PR.

278

Tableau F4 – Appréciation de la preuve pour la Dermatologie


Population : Personnes sous traitement par un médicament biologique atteint d’une maladie dermatologique (Psoriasis en plaques) Intervention : Transfert d’un médicament biologique de référence vers un médicament biosimilaire (ou vice versa) ou de deux médicaments biosimilaires entre eux. Comparaison : Aucun transfert (maintien du traitement)








n = 828 (3 ECRA)


Modérée

Quantité d’études : 3 études Plan d’étude : ECRA Risque de biais : Faible; sélection et co-médication différente. Précision : Modérée (analyse statistique adéquate), manque de puissance

Modérée Cohérence Très élevée Toutes les études sont cohérentes. Aucune des différences obtenues n’est statistiquement significative.



Généralisabilité Élevée Études réalisées sur des populations en Amérique du Nord, en Europe, Australie et Russie dans plusieurs établissements pour les ECRA (un total de 97 établissements).

Immunogénicité





Modérée

Quantité d’études : 5 études Plan d’étude : ECRA, ECRA Jorgensen (6 indications) Risque de biais : Faible; sélection et co-médication différente. Précision : Modérée (analyse statistique adéquate)





Généralisabilité Élevée Études réalisées sur des populations en Amérique du Nord, en Europe, Australie, Afrique du Sud et Russie dans plusieurs établissements pour les ECRA (219 établissements).





Modérée









n = 1 789 (4 ECRA)


Modérée Quantité d’études : 5 études Plan d’étude : ECRA, ECRA Jorgensen (6 indications) Risque de biais : Faible; sélection et co-médication différente.

Modéré

279






n = 482 (ECRA Jorgensen)

Précision : Modérée (analyse statistique adéquate)






n = 1789 (4 ECRA) n = 482 (ECRA Jorgensen)


Modérée






Généralisabilité Élevée Études réalisées sur des populations européenne et américaines dans plusieurs établissements pour les ECRA (219 établissements).

280

Tableau F5 – Appréciation de la preuve pour l’Oncologie (prévention de la neutropénie)


Population : Personnes sous traitement par un médicament biologique en oncologie. Intervention : Transfert d’un médicament biologique de référence vers un médicament biosimilaire (ou vice versa) ou de deux médicaments biosimilaires entre eux. Comparaison : Aucun transfert (maintien du traitement)








n =214 (1 ECRA)


Modéré

Quantité d’études : 1 étude Plan d’étude : ECRA Risque de biais : Faible; risques de biais de sélection et de performance. Précision : Faible (analyse statistique adéquate, aucun calcul de puissance). Faible

Cohérence Non applicable Une seule étude



Généralisabilité Modéré Étude réalisée sur des populations européenne et russe dans plusieurs établissements le ECRA (26 établissements).

Immunogénicité



n =214 (1 ECRA)


Modéré








n =214 (1 ECRA)


Modéré






281








n =214 (1 ECRA)


Modéré







n =214 (1 ECRA)


Modéré






282

Tableau F6 – Appréciation de la preuve pour l’Oncologie (cancer du sein, HER2 positif)


Population : Personnes sous traitement par un médicament biologique en oncologie. Intervention : Transfert d’un médicament biologique de référence vers un médicament biosimilaire (ou vice versa) ou de deux médicaments biosimilaires entre eux. Comparaison : Aucun transfert (maintien du traitement)







Les données sont insuffisantes pour conclure

S.O.


S.O.

Quantité d’études : S.O. Plan d’étude : S.O. Risque de biais : S.O. Précision : S.O.

Insuffisant Cohérence S.O. S.O.


S.O. S.O.

Généralisabilité S.O. S.O.

Immunogénicité



S.O.


S.O.

Quantité d’études : S.O. Plan d’étude : S.O. Risque de biais : S.O. Précision : S.O.

Insuffisant Cohérence S.O. S.O.


S.O. S.O.

Généralisabilité S.O. S.O.



n =725 (1 ECRA)


Faible

Quantité d’études : 1 étude Plan d’étude : ECRA Risque de biais : Faible; risques de biais de sélection et détection et de performance. Précision : faible (analyse statistique adéquate, analyse de puissance dans une étude) Faible




Généralisabilité Faible Études réalisées sur des populations en Europe, au Canada, Brésil et Afrique du Sud dans 97 établissements.

283








n =725 (1 ECRA)


Faible







n =725 (1 ECRA)


Faible






284

Tableau F7 – Appréciation de la preuve pour la Hématologie/Néphrologie


Population : Personnes sous traitement par un médicament biologique hémodialysées suite à une anémie causée par une maladie rénale chronique. Intervention : Transfert d’un médicament biologique de référence vers un médicament biosimilaire (ou vice versa) ou de deux médicaments biosimilaires entre eux. Comparaison : Aucun transfert (maintien du traitement)








n = 5 402 (2 ECRA; 2 cohortes rétrospectives)


Élevée

Quantité d’études : 4 études Plan d’étude : ECRA, cohorte Risque de biais : Faible; certains biais sont présents devis ouvert, dosage variable, pertes de patients élevée. Précision : Élevée (analyse statistique adéquate généralement présente, puissance suffisante)

Modéré Cohérence Modéré Aucune différence statistiquement significative dans 3 études sur 4. Une étude montre une différence statistiquement significative en faveur de l’usage du BR.




Études réalisées sur des populations aux États-Unis, en Allemagne et en Autriche dans plusieurs établissements pour les ECRA (102 établissements). Pour les cohortes les études ont été réalisées en Italie.

Immunogénicité Présence d’AAM et AAMN


n = 478 (1 ECRA)


Élevée

Quantité d’études : 1 étude Plan d’étude : ECRA Risque de biais : Faible; certains biais sont présents : dosage variable, pertes de patients élevée. Précision : Élevée (analyse statistique adéquate généralement présente, puissance suffisante)

Faible Cohérence Non applicable Une seule étude



Généralisabilité Modérée Études réalisées sur des populations en Allemagne et en Autriche dans plusieurs établissements (56 établissements).

285








n = 4 598 (1 ECRA, 1 cohorte rétrospective)


Modérée

Quantité d’études : 2 études Plan d’étude : ECRA, cohorte Risque de biais : Faible; certains biais sont présents devis ouvert, dosage variable, pertes de patients élevée. Précision : faible (pas d’analyses statistiques et données secondaires)

Modéré Cohérence Élevée




Généralisabilité Élevée Études réalisées en Italie et aux États-Unis, dans plusieurs établissements (47).



n = 432 (1 ECRA)


Modérée

Quantité d’études : 1 étude Plan d’étude : ECRA Risque de biais : Faible; certains biais sont présents devis ouvert, dosage variable, pertes de patients élevée. Précision : faible (pas d’analyses statistiques et données secondaires) Modéré




Généralisabilité Élevée Études réalisées aux États-Unis, dans plusieurs établissements (46).


n = 910 (2 ECRA)


Élevée

Quantité d’études : 2 études Plan d’étude : ECRA Risque de biais : Faible; certains biais sont présents devis ouvert, dosage variable, pertes de patients élevée. Précision : Élevée (analyse statistique adéquate généralement présente, puissance suffisante)

Élevé Cohérence Élevée




Généralisabilité Élevée Études réalisées sur des populations aux États-Unis, en Allemagne et en Autriche et dans plusieurs établissements (102).

286

Tableau F8 – Appréciation de la preuve pour l’Endocrinologie (Diabète)


Population : Personnes sous traitement par un médicament biologique atteint de diabète de type 1 ou 2. Intervention : Transfert d’un médicament biologique de référence vers un médicament biosimilaire (ou vice versa) ou de deux médicaments biosimilaires entre eux. Comparaison : Aucun transfert (maintien du traitement)








n =660 (2 ECRA, analyse post-hoc)


Élevée

Quantité d’études : 3 études Plan d’étude : ECRA, analyse post-hoc de ECRA Risque de biais : Faible; sélection et co-médication différente Précision : Modérée (analyse statistique adéquate, calcul de puissance manquant)

Élevé Cohérence Très élevée





Études réalisées sur des populations en Europe, aux États-Unis, République de Corée, Taiwan, Mexique, Afrique du Sud dans plusieurs établissements pour les ECRA (un total de 195 établissements).

Immunogénicité



n =877 (1 ECRA, analyse post-hoc)


Élevée

Quantité d’études : 2 études Plan d’étude : ECRA, analyse post-hoc de ECRA Risque de biais : Faible; sélection et co-médication différente Précision : Modérée (analyse statistique adéquate calcul de puissance manquant)

Modéré Cohérence Élevée






287








n = 877 (1 ECRA, analyse post-hoc)


Élevée


Modérée Cohérence Élevée








n = 877 (1 ECRA, analyse post-hoc)


Élevée


Faible Cohérence Faible

Les études sont incohérentes. Aucune des différences obtenues n’est statistiquement significative pour une étude et l’autre favorise le BS.






n = 127 (1 ECRA)


Élevée

Quantité d’études : 1 étude Plan d’étude : ECRA Risque de biais : Faible; sélection et co-médication différente Précision : Modérée (analyse statistique adéquate, absence de calcul de puissance)

Faible Cohérence Non applicable Une seule étude.



Généralisabilité Modérée Études réalisées sur des populations en Europe et États-Unis dans plusieurs établissements (81établissements). Population atteinte de diabète de type 1 seulement.

288

Tableau F9 – Appréciation de la preuve pour des substitutions multiples


Population : Personnes sous traitement par un médicament biologique. Intervention : Transfert d’un médicament biologique de référence vers un médicament biosimilaire (ou vice versa) ou de deux médicaments biosimilaires entre eux de façon multiple. Comparaison : Aucun transfert (maintien du traitement)


Transfert : BR vers BS ou BS vers BR, plus

d’une fois






n =341 (2 ECRA)


Faible

Quantité d’études : 2 études Plan d’étude : ECRA Risque de biais : Faible; sélection et co-médication différente Précision : Faible (analyse statistique faible, manque de puissance)

Insuffisant

Cohérence Modérée Toutes les études sont cohérentes. Aucune des différences obtenues n’est statistiquement significative.


Modéré L’objectif de l’intervention était de démontré une similarité entre les 2 traitements. L’impact clinique est similaire.

Généralisabilité Insuffisante

Études réalisées principalement sur des populations en Europe et aux États-Unis, dans plusieurs établissements (un total de 107 établissements) pour des sujets atteints de DT1 et cancer du sein (neutropénie). Aucune étude recensée pour la gastroentérologie, rhumatologie, dermatologie, hématologie, néphrologie.

Immunogénicité



n =1337 (4 ECRA)


Modérée

Quantité d’études : 4 études Plan d’étude : ECRA Risque de biais : Faible; sélection et co-médication différente Précision : Faible (analyse statistique faible)

Insuffisant

Cohérence Élevée Toutes les études sont cohérentes. Aucune des différences obtenues n’est statistiquement significative.




Études réalisées principalement sur des populations en Europe et aux États-Unis, (un total de 254 établissements) pour des sujets atteint de Ps, DT1 et cancer du sein (neutropénie). Aucune étude recensée pour la gastroentérologie, rhumatologie, hématologie néphrologie.

289


Transfert : BR vers BS ou BS vers BR, plus

d’une fois






n =1337 (4 ECRA)


Modérée


Insuffisant





Études réalisées principalement sur des populations en Europe et aux États-Unis, dans plusieurs établissements (un total de 107 établissements) pour des sujets atteint de DT1 et cancer du sein (neutropénie). Aucune étude recensée pour la gastroentérologie, rhumatologie, dermatologie, hématologie, néphrologie.



n =1337 (4 ECRA)


Élevée

Quantité d’études : 4 études Plan d’étude : ECRA Risque de biais : Faible; sélection et co-médication différente Précision : Modérée (analyse statistique adéquate)

Insuffisant




Généralisabilité Très faible

Études réalisées principalement sur des populations en Europe et aux États-Unis, dans plusieurs établissements (un total de 107 établissements) pour des sujets atteint de DT1 et cancer du sein (neutropénie). Aucune étude recensée pour la gastroentérologie, rhumatologie, dermatologie, hématologie, néphrologie.

Taux de rétention Les données sont insuffisantes pour conclure

n =1337 (4 ECRA)


Modérée


Insuffisant





Études réalisées principalement sur des populations en Europe et aux États-Unis, (un total de 254 établissements) pour des sujets atteint de Ps, DT1 et cancer du sein (neutropénie). Aucune étude recensée pour la gastroentérologie, rhumatologie, hématologie néphrologie.

290

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Innocuité de la substitution et de l’interchangeabilité des … · 2020-06-01 · Le présent document contient les annexes complémentaires au rapport Innocuité de la substitution