Impact of methodological choices in comparative effectiveness studies: application in natalizumab versus fingolimod comparison among patients with multiple sclerosis

M Lefort # 1 2, S Sharmin # 3 4, J B Andersen # 5, S Vukusic 6 7 8, R Casey 6 7 8 9, M Debouverie 10, G Edan 11, J Ciron 12, A Ruet 13, J De Sèze 14, E Maillart 15, H Zephir 16, P Labauge 17, G Defer 18, C Lebrun-Frenay 19, T Moreau 20, E Berger 21, P Clavelou 22, J Pelletier 23, B Stankoff 24, O Gout 25, E Thouvenot 26, O Heinzlef 27, A Al-Khedr 28, B Bourre 29, O Casez 30, P Cabre 31, A Montcuquet 32, A Wahab 33, J P Camdessanché 34, A Maurousset 35, H Ben Nasr 36, K Hankiewicz 37, C Pottier 38, N Maubeuge 39, D Dimitri-Boulos 40, C Nifle 41, D A Laplaud 42 43, D Horakova 44, E K Havrdova 44, R Alroughani 45, G Izquierdo 46, S Eichau 46, S Ozakbas 47, F Patti 48 49, M Onofrj 50, A Lugaresi 51 52, M Terzi 53, P Grammond 54, F Grand'Maison 55, B Yamout 56, A Prat 57 58, M Girard 57 58, P Duquette 57 58, C Boz 59, M Trojano 60, P McCombe 61 62, M Slee 63, J Lechner-Scott 64 65, R Turkoglu 66, P Sola 67, D Ferraro 67, F Granella 68 69, V Shaygannejad 70, J Prevost 71, D Maimone 72, O Skibina 73, K Buzzard 73, A Van der Walt 73, R Karabudak 74, B Van Wijmeersch 75, T Csepany 76, D Spitaleri 77, S Vucic 78, N Koch-Henriksen 79, F Sellebjerg 80, P S Soerensen 80, C C Hilt Christensen 81, P V Rasmussen 82, M B Jensen 83, J L Frederiksen 84, S Bramow 80, H K Mathiesen 85, K I Schreiber 80, H Butzkueven 86 87 88, M Magyari # 4 80, T Kalincik # 89, E Leray # 90 91

Affiliations

doi: 10.1186/s12874-022-01623-8

Abstract

Background: Natalizumab and fingolimod are used as high-efficacy treatments in relapsing-remitting multiple sclerosis. Several observational studies comparing these two drugs have shown variable results, using different methods to control treatment indication bias and manage censoring. The objective of this empirical study was to elucidate the impact of methods of causal inference on the results of comparative effectiveness studies.

Methods: Data from three observational multiple sclerosis registries (MSBase, the Danish MS Registry and French OFSEP registry) were combined. Four clinical outcomes were studied. Propensity scores were used to match or weigh the compared groups, allowing for estimating average treatment effect for treated or average treatment effect for the entire population. Analyses were conducted both in intention-to-treat and per-protocol frameworks. The impact of the positivity assumption was also assessed.

Results: Overall, 5,148 relapsing-remitting multiple sclerosis patients were included. In this well-powered sample, the 95% confidence intervals of the estimates overlapped widely. Propensity scores weighting and propensity scores matching procedures led to consistent results. Some differences were observed between average treatment effect for the entire population and average treatment effect for treated estimates. Intention-to-treat analyses were more conservative than per-protocol analyses. The most pronounced irregularities in outcomes and propensity scores were introduced by violation of the positivity assumption.

Conclusions: This applied study elucidates the influence of methodological decisions on the results of comparative effectiveness studies of treatments for multiple sclerosis. According to our results, there are no material differences between conclusions obtained with propensity scores matching or propensity scores weighting given that a study is sufficiently powered, models are correctly specified and positivity assumption is fulfilled.

Keywords: Causal contrasts; Censoring; Effectiveness; Indication bias; Multiple sclerosis; Positivity assumption; Propensity score.

© 2022. The Author(s).

Conflict of interest statement

OFSEP: The authors report the following relationships: speaker honoraria, advisory board or steering committee fees, independent data monitoring committees fee, consultancy and lecturing fees, principal investigator in clinical trials, research support, unconditional PhD donation and/or conference travel support from Actelion (PC, ET), Ad Scientiam (EM), Akcea (JPC), Alnylam (JPC), Almirall (OH), Bayer (GE, HZ, OH), Biogen (GE, JC, AR, JDS, EM, HZ, PL, GD, TM, EB, PC, JP, BS, ET, OH, BB, OC, AMo, JPC, AMa, IP, NM, DAL, SV, WA), Celgene (JC, ET, DAL), CSL-Behring (JPC), FHU Imminent (HZ), Geneuro (SV), Genzyme-Sanofi (GE, JC, AR, JDS, EM, HZ, PL, GD, CLF, TM, EB, PC, JP, BS, ET, OH, BB, OC, AMo, JPC, AMa, IP, NM, DAL, SV), Grifols (JPC), Laboratoire Français des Biotechnologies (JPC), LFB (GE), LFSEP (HZ), Merck / EMD (GE, JC, AR, EM, HZ, PL, GD, PC, JP, BS, ET, OH, BB, OC, AMo, JPC, AMa, NM, DAL, SV), Medday (EL, AR, TM, PC, JP, DAL, SV), Natus (JPC), Novartis (EL, GE, JC, AR, JDS, EM, HZ, PL, GD, CLF, TM, EB, PC, JP, BS, ET, OH, BB, OC, AMo, JPC, AMa, IP, NM, DAL, SV), Pfizer (JPC), Pharmalliance (JPC), Roche (ML, EL, GE, JC, AR, JDS, EM, HZ, PL, GD, CLF, EB, PC, JP, BS, ET, OH, BB, OC, AMa, NM, DAL, SV, WA), SNF-Floerger (JPC), Teva (GE, JC, AR, JDS, EM, HZ, PL, GD, EB, PC, JP, ET, OH, BB, AMo, JPC, AMa, SV), Académie de Médecine (HZ), Agence Nationale de la Recherche (DAL), French National Security Agency of Medicines and Health Products (EL), the EDMUS Foundation (EL), the ARSEP foundation (GE, HZ, ET, DAL,ML), PHRC Foundation (ET), Rennes University Hospital (GE). MSBase: The authors report the following relationships: speaker honoraria, advisory board or steering committee fees, research support and/or conference travel support from Actelion (EKH), Almirall (GI, FP, MT), Bayer (RA, FP, AL, MT, CB, MT, MS, JLS, BVW, TC, DS), BioCSL (KB, TK), Biogen (DH, EKH, RA, GI, FP, AL, PG, FGM, MG, PD, CB, MT, MS, JLS, PS, DF, FG, JP, BVW, TC, HB, TK), Canadian Multiple sclerosis society (PG, PD), Canadian Institutes of Health Research (MG, PD), Celgene (EKH, FP, TK), Czech Minsitry of Education (DH, EKH), Fondazione Italiana Sclerosi Multipla (FP, AL), Grifols (KB), Genzyme-Sanofi (DH, EKH, RA, GI, FP, AL, MT, PG, FGM, MG, PD, CB, MT, MS, JLS, PS, DF, FG, JP, BVW, TC, DS, HB, TK), GSK (RA), Merck / EMD (DH, EKH, RA, GI, FP, AL, MT, PG, MG, PD, CB, MT, MS, JLS, PS, DF, FG, KB, BVW, TC, DS, HB, TK), Mitsubishi (FGM), Ministero Italiano della Universit e della Ricerca Scientifica (FP), Mylan (FP, AL), Novartis (DH, EKH, RA, GI, FP, AL, MT, PG, FGM, MG, PD, CB, MT, MS, JLS, PS, DF, FG, JP, KB, BVW, TC, DS, HB, TK), ONO Pharmaceuticals (FGM), Roche (DH, EKH, RA, GI, FP, AL, MT, CB, FG, KB, BVW, TC, TK), Teva (DH, EKH, GI, FP, AL, MT, PG, FGM, MG, PD, CB, MT, JLS, PS, DF, JP, KB, BVW, TC, DS, TK), WebMD Global (TK). DMSR: The authors report the following relationships: speaker honoraria, advisory board or steering committee fees, independent data monitoring committees fee, consultancy fee, research support and/or conference travel support from Almirall (JF), Alexion (PVR), Bayer (HKM), Biogen (NKH, FS, CH, PVR, MBJ, JF, SB, HKM, KIS, MM), Bristol Myers Squibb (PVR), Celgene (PSS), Genzyme-Sanofi (FS, PSS, CH, PVR, MBJ, JF, SB, HKM, KIS, MM), GSK (PSS), Medday (PSS), Merck / EMD (JBA, NKH, FS, PSS, CH, PVR, MBJ, JF, SB, HKM, KIS, MM), Novartis (NKH, FS, PSS, CH, PVR, MBJ, JF, KIS, MM), Roche (FS, CH, PVR, MBJ, JF, SB, KIS, MM), Teva (NKH, FS, PSS, PVR, MBJ, JF, HKM, KIS, MM).

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