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Observational Study
. 2026 Jan 13;97(2):165-174.
doi: 10.1136/jnnp-2025-336762.

Target trial emulation to replicate randomised clinical trials using registry data in multiple sclerosis

Antoine Gavoille  1   2   3 , Mikail Nourredine  2   3 , Fabien Rollot  4   5   6   7 , Romain Casey  4   5   6   7 , Guillaume Mathey  8   9   10 , Anne Kerbrat  11   12 , Jonathan Ciron  13   14 , Jérôme De Sèze  15 , Bruno Stankoff  16 , Elisabeth Maillart  17 , Aurelie Ruet  18   19 , Pierre Labauge  20 , Arnaud Kwiatkowski  21 , Helene Zephir  22 , Caroline Papeix  23 , Gilles Defer  24 , Christine Lebrun-Frenay  25 , Thibault Moreau  26 , David-Axel Laplaud  27 , Eric Berger  28 , Pierre Clavelou  29   30 , Eric Thouvenot  31   32 , Olivier Heinzlef  33 , Jean Pelletier  34 , Abdullatif Al Khedr  35 , Olivier Casez  36   37 , Bertrand Bourre  38 , Abir Wahab  39 , Laurent Magy  40 , Solène Moulin  41 , Jean-Philippe Camdessanché  42 , Ines Doghri  43 , Mariana Sarov  44 , Karolina Hankiewicz  45 , Corinne Pottier  46 , Amélie Dos Santos  47   48 , Eric Manchon  49 , Maia Tchikviladze  50   51 , Muriel Rabilloud  2   3 , Fabien Subtil  2   3 , Sandra Vukusic  4   5   6   7
Affiliations
Observational Study

Target trial emulation to replicate randomised clinical trials using registry data in multiple sclerosis

Antoine Gavoille et al. J Neurol Neurosurg Psychiatry. .

Abstract

BackgroundTarget trial emulation (TTE) offers a formal framework for causal inference using observational data, but its validity must be evaluated in each research domain by replicating randomised clinical trials (RCTs). We aimed to replicate eight RCTs evaluating the efficacy of disease-modifying therapies (DMTs) in multiple sclerosis (MS) using French registry data.

Methods: This multicentre, retrospective, observational study was conducted using data extracted in December 2023 from the Observatoire Français de la Sclérose en Plaques (OFSEP) database. For each emulated trial, patients were included when they initiated one of the DMT evaluated in the corresponding RCT and met its inclusion criteria. Clinical outcomes were the annualised relapse rate and 3-month confirmed Expanded Disability Status Scale progression. Radiological outcomes were new/enlarged T2-lesions and new gadolinium-enhanced T1-lesions on a brain MRI. A targeted maximum likelihood estimator was used to estimate the treatment effect adjusted for confounding factors between groups and corrected for censoring and missing outcome assessment.

Results: 14 111 patients were included in eight emulated trials: ASSESS (fingolimod vs glatiramer acetate), BEYOND (interferon beta vs glatiramer acetate), CONFIRM (dimethyl fumarate (DMF) vs glatiramer acetate), OPERA (ocrelizumab vs interferon beta), REGARD (interferon beta vs glatiramer acetate), RIFUND-MS (rituximab vs DMF), TENERE (teriflunomide vs interferon beta) and TRANSFORMS (fingolimod vs interferon beta). Treatment effects estimated in emulated trials were concordant with RCT findings in seven of eight trials for relapse rate, and in all six trials assessing disability progression. Radiological outcomes were more challenging to replicate; concordance was achieved in three of five trials for new T2-lesions, and one of four trials for new gadolinium-enhanced T1-lesions.

Conclusion: The combined use of a TTE methodology and high-quality registry data is a valid tool to evaluate treatment effectiveness in MS.

Keywords: MULTIPLE SCLEROSIS; NEUROEPIDEMIOLOGY; STATISTICS.

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Conflict of interest statement

Competing interests: AG, MN, FR, AnK, CL-F, JP, SM, MS, KH, CP, ADS, EM, MT, MR, FS: no disclosure. GM: consulting or lectures fees, travel grants from Biogen, Novartis, Sanofi-Genzyme, Merck, Teva, Alexion, and Roche. JC: consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis, Merck, Sanofi-Genzyme, Roche, Alexion and Horizon-Amgen. JDS: consulting and lecturing fees, travel grants and unconditional research support from Biogen, Novartis, Roche, Sanofi-Genzyme, and Teva. BS: consulting and lecturing fees, travel grants from Biogen Idec, Merck-Serono, Novartis, Genzyme, and unconditional research support from Merck-Serono, Genzyme, and Roche. EM: research support from Biogen and ARSEP foundation, and consulting and lecturing fees or serving on scientific advisory boards from Biogen, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme, Teva. AR: received funding for travel or received speaker honoraria from Biogen, Merck, Alexion, Novartis, and Sanofi-Genzyme; served as consultant for Horizon; received research support from Biogen, BMS, Sanofi-Genzyme, Roche, Merck. PL: fees and grants from Biogen, Sanofi-Genzyme, Novartis, Alexion, Merck. ArK: consulting or lectures, and invitations for national and international congresses from Biogen, Janssen, Merck, Sandoz, Sanofi-Genzyme, Novartis and Roche. HZ: consulting or lectures, and invitations for national and international congresses from Biogen, Merck, Teva, Sanofi-Genzyme, Novartis and Bayer; research support from Teva and Roche, academic research grants from Académie de Médecine, LFSEP, FHU Imminent and ARSEP Foundation. CP: lecturing fees or served on scientific advisory boards for Novartis and Biogen. GD: consulting and lecturing fees for Biogen, Novartis, Merck, Roche and Teva and funding for travel from Merck, Biogen, Sanofi-Genzyme, Novartis and Teva; research supporting from Merck, Biogen, and Novartis. TM: fees as scientific adviser from Biogen, Medday, Novartis, Sanofi-Genzyme. D-AL: served on scientific advisory boards for Alexion, BMS, Roche, Sanofi-Genzyme, Novartis, Merck, Janssen and Biogen, received conference travel support and/or speaker honoraria from Alexion, Novartis, Biogen, Roche, Sanofi-Genzyme, BMS and Merck and received research support from Fondation ARSEP, Fondation EDMUS and Agence Nationale de la Recherche. EB: honoraria and consulting fees from Novartis, Sanofi-Genzyme, Biogen, Merck, Roche and Teva. PC: consulting and lecturing fees, travel grants and unconditional research support from Biogen, Janssen, Medday, Merck, Novartis, Roche, Sanofi-Genzyme and Teva. ET: consulting and lecturing fees, travel grants or unconditional research support from the following pharmaceutical companies: Actelion, Biogen, BMS, Janssen, Merck, Novartis, Roche, Sanofi-Genzyme. OH: consulting and lecturing fees from Bayer Schering, Merck, Teva, Sanofi-Genzyme, Novartis, Almirall and BiogenIdec, travel grants from Novartis, Teva, Sanofi-Genzyme, Merck and Biogen; research support from Roche, Merck and Novartis. AAK: consulting or lectures, and invitations for national and international congresses from Biogen, Merck, Sandoz, Sanofi-Genzyme, Alexion, Novartis, and Roche. OC: received consulting fees and travelling/congress fees from Biogen, Roche, Merck, Novartis, Jansen, Sanofi-Genzyme. BB: served on scientific advisory board for Alexion, BMS, Biogen, Sanofi-Genzyme, Janssen, Merck, Horizon, Novartis, Roche, Sandoz, and received funding for travel and honoraria from Alexion, Merck, Novartis, Sanofi-Genzyme, Rocheand Janssen. AW: received consulting fees and travelling/congress fees from Roche, Merck, Novartis, Janssen. LM: consulting fees and travelling fees from Alexion, Alnylam, Argenx, Biogen, CSL Behring, LFB, Merck, Novartis, Pfizer, Roche, Sanofi-Genzyme. J-PC: consulting and lecturing fees from Akcea, Alexion, Alnylam, Argenx, Biogen, Bristol Myers Squibb, CSL-Behring, Sanofi-Genzyme, GSK, Grifols, Laboratoire Français des Biotechnologies, Merck, Natus, Novartis, Pfizer, Pharmalliance, UCB Pharma, Teva, SNF-Floerger; travel grants from Akcea, Alexion, Alnylam, Argenx, Biogen, CSL-Behring, Sanofi-Genzyme, Grifols, Laboratoire Français des Biotechnologies, Merck, Natus, Novartis, Pfizer, Teva, SNF-Floerger. ID: consulting, lecturing fees, travel grants or unconditional research support from Merck, Sanofi-Genzyme, Sandoz, Novartis, Alexion, Horizon. SV: lecturing fees, travel grants and research support from Biogen, BMS-Celgene, Janssen, Merck, Novartis, Roche, Sandoz, Sanofi-Genzyme.

Figures

Figure 1
Figure 1. Concordance between the treatment effect estimated in emulated trials and RCTs according to outcome EA: the adjusted effect estimated in the emulated trial is contained within the 95% CI of the RCT estimate; standardised difference agreement: the adjusted effect estimated in the emulated trial is not statistically different from the RCT estimate using a z-test. ASSESS, fingolimod vs glatiramer acetate; BEYOND, interferon beta vs glatiramer acetate; CONFIRM, DMF vs glatiramer acetate; DMF, dimethyl fumarate; EA, estimate agreement; EDSS, expanded disability status scale; OPERA, ocrelizumab vs interferon beta; RCT, randomised clinical trial; REGARD, interferon beta vs glatiramer acetate; RIFUND-MS, rituximab vs DMF; SDA, standardised difference agreement; TENEREvs interferon beta; TRANSFORMSvs interferon beta.
Figure 2
Figure 2. Treatment effect estimated in emulated trials and RCTs according to outcome, before and after adjustment for confounding factors. Coloured boxes indicate RCT estimates (estimate and 95% CI) and are coloured according to the concordance between emulated trial and RCT estimates. ARR, annualised relapse rate; ASSESS, fingolimod vs glatiramer acetate; BEYOND, interferon beta vs glatiramer acetate; CONFIRM, DMF vs glatiramer acetate; EA, estimate agreement; EDSS, expanded disability status scale; OPERA, ocrelizumab vs interferon beta; RCT, randomised clinical trial; REGARD, interferon beta vs glatiramer acetate; RIFUND-MS, rituximab vs DMF; SDA, standardised difference agreement; TENERE, teriflunomide vs interferon beta; TMLE, targeted maximum likelihood estimator; TRANSFORMS, fingolimod vs interferon beta.
See this image and copyright information in PMC

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