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Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis
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  • Published on:
    Response to: Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis: when methodology does not hold the promise
    • Tomas Kalincik, Neurologist, Biostatistician CORe, Department of Medicine, University of Melbourne, Melbourne, Australia; Royal Melbourne Hospital, Melbourne, Australia
    • Other Contributors:
      • Charles Malpas, Psychologist, Biostatistician
      • Sifat Sharmin, Statistician
      • Tim Spelman, Biostatistician
      • Eva K Havrdova, Neurologist
      • Dana Horakova, Neurologist
      • Guillermo Izquierdo, Neurologist
      • Alexandre Prat, Neurologist
      • Marc Girard, Neurologist
      • Pierre Duquette, Neurologist
      • Pierre Grammond, Neurologist
      • Marco Onofrj, Neurologist
      • Alessandra Lugaresi, Neurologist
      • Serkan Ozakbas, Neurologist
      • Ludwig Kappos, Neurologist
      • Jens Kuhle, Neurologist
      • Murat Terzi, Neurologist
      • Jeannette Lechner-Scott, Neurologist
      • Cavit Boz, Neurologist
      • Francois Grand'Maison, Neurologist
      • Julie Prevost, Neurologist
      • Patrizia Sola, Neurologist
      • Diana Ferraro, Neurologist
      • Franco Granella, Neurologist
      • Maria Trojano, Neurologist
      • Roberto Bergamaschi, Neurologist
      • Eugenio Pucci, Neurologist
      • Recai Turkoglu, Neurologist
      • Pamela McCombe, Neurologist
      • Vincent Van Pesch, Neurologist
      • Bart Van Wijmeersch, Neurologist
      • Claudio Solaro, Neurologist
      • Cristina Ramo-Tello, Neurologist
      • Mark Slee, Neurologist
      • Raed Alroughani, Neurologist
      • Bassem Yamout, Neurologist
      • Vahid Shaygannejad, Neurologist
      • Daniele Spitaleri, Neurologist
      • Jose Luis Sanchez-Menoyo, Neurologist
      • Radek Ampapa, Neurologist
      • Suzanne Hodgkinson, Neurologist
      • Rana Karabudak, Neurologist
      • Ernest Butler, Neurologist
      • Steve Vucic, Neurologist
      • Vilija Jokubaitis, Neurologist
      • Helmut Butzkueven, Neurologist

    We thank Dr Platt and colleagues for their critical review of our work, especially of the methodology that we have used in this study. It is understandable that comparative studies of treatment effectiveness trigger constructive discussions among industry and academics. We also vehemently agree that rigorous methodology and cautious interpretation of results is mandatory, especially for analyses of observational data.1 2 Therefore, in this letter, we will provide additional clarifications in response to the concerns raised.

    We appreciate that the categories that are underrepresented in multivariable logistic regression models may lead to inflation of estimates of the corresponding coefficients and their variance. Such inflation would, however, result in an overly conservative matching rather than the opposite. Due to the use of a caliper, patients with an extreme propensity score can not be matched to patients within the bulk of the distribution of the propensity scores. Such patients were excluded from the matched cohorts.

    The issue of residual imbalance is important in any non-randomised comparative study. We acknowledge that the standardised mean difference in annualised relapse rates (ARR) between teriflunomide and fingolimod exceeded the nominal threshold of 20%. It is therefore reassuring that the sensitivity analyses, in which the residual imbalance fell below the accepted threshold of 20% (patients with prior on-treatment relapses, Cohen’s d 14%, and...

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    Conflict of Interest:
    Neither this response nor the original study were financially supported by industry.
    The authors have received research funding, speaker honoraria, travel support, and have served on advisory boards and steering committees equally for Biogen, Novartis and Sanofi Genzyme.
  • Published on:
    Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis: when methodology does not hold the promise
    • Robert W Platt, Professor Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada
    • Other Contributors:
      • Mohammad E Karim, Assistant Professor
      • Thomas PA Debray, Assistant Professor
      • Massimiliano Copetti, Biostatistician, Head
      • Georgios Tsivgoulis, Professor
      • Emmanuelle Waubant, Neurologist
      • Hans P Hartung, Professor

    Dear Editor,

    We read with interest the article by Kalincik et al. [1] comparing fingolimod, dimethyl fumarate and teriflunomide in a cohort of relapsing-remitting multiple sclerosis (MS) patients. The authors investigated several endpoints and performed various sensitivity analyses, and we commend them for reporting technical details in the online supplementary material. We, however, have some concerns about the design, analysis and reporting of the study.

    1. In the primary analyses, three separate propensity score models were developed to construct a matched cohort for each of the three pairwise comparisons. Supplementary Table 6 clearly indicates the existence of zero or low frequencies in some variables (e.g., most active previous therapy and magnetic resonance imaging [MRI] T2 lesions). Yet, those variables were used as covariates in the propensity score models, unsurprisingly resulting in extremely high point estimates and standard errors (SE; as reported in Supplementary Table 7). For example, teriflunomide was not the most active therapy for any patient in the dimethyl fumarate cohort (n=0 from Supplementary Table 6), but that category was nevertheless included in the propensity score model, leading to an unrealistic point estimate of 18.65 with SE of 434.5 (Supplementary Table 7). Even higher SEs (greater than 1000) are observed in the other propensity score models. Propensity scores estimated from these poorly constructed models were then used to cr...

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    Conflict of Interest:
    RW Platt has received consulting fees from Biogen and has participated in advisory boards for Biogen. He has received consulting fees from Amgen, Depuy, Eli Lilly, Merck, and Pfizer for projects unrelated to the current work.
    MEK has received consulting fees from Biogen and participated in advisory Boards and/or Satellite Symposia of Biogen.
    TPA Debray received consulting fees from Biogen and participated in advisory Boards and/or Satellite Symposia of Biogen.
    M Copetti received consulting fees from Biogen, Intercept, Eisai and Teva and participated in advisory Boards and/or Satellite Symposia of Biogen.
    G Tsivgoulis has received travel grant support and/or has participated in advisory Boards and/or Satellite Symposia of Biogen, Merck, Bayer, Teva, Sanofi and Roche
    E Waubant has received honoraria for talks from Medscape and The Corpus. She has funding from PCORI, NMSS, NIH, and the Race to Erase MS. She is site PI for trials with Biogen, Novartis and Roche. She is section editor for Annals in Clinical and Transnational Neurology and co-editor in chief for MS and Related Disorders.
    HP Hartung received honoraria for serving on steering and data monitoring committees, consulting and speaking from BayerHealthcare, Biogen, Geneuro, Merck, Novartis, Receptos Celgene, Roche, Sanofi Genzyme, Teva, TG Therapeutics with approval by the Rector of Heinrich-Heine-University.