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      Head-to-head drug comparisons in multiple sclerosis : Urgent action needed

      , , , , , ,
      Neurology
      Ovid Technologies (Wolters Kluwer Health)

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          Abstract

          Disease-modifying drugs are changing the natural history of multiple sclerosis (MS). However, currently available clinical trial data are insufficient to develop accurate personalized treatment algorithms to assign the best possible treatment to each person with MS according to disease features, treatment history, and comorbidities. Such accurate algorithms would require the presence of numerous head-to-head trials of long duration, which is virtually impossible, given the economic costs, required time, and difficulties with attrition. Thus, efforts are being made to compare relative treatment efficacy through observational designs, using large multicenter prospective cohorts or “big MS data,” and network meta-analyses. Although such studies can yield useful information, they are liable to biases and their results should be confirmed in other study populations, including smaller, single-center cohorts, where some of these biases can be minimized. In this View article, we analyze the potential benefits and biases of all these strategies alternative to head-to-head trials in MS. Finally, we propose the combination of all these types of studies to obtain reliable head-to-head drug comparisons in the absence of randomized designs.

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          The number of subjects per variable required in linear regression analyses.

          To determine the number of independent variables that can be included in a linear regression model.
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            Methods for constructing and assessing propensity scores.

            To model the steps involved in preparing for and carrying out propensity score analyses by providing step-by-step guidance and Stata code applied to an empirical dataset.
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              Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses.

              To determine the validity of adjusted indirect comparisons by using data from published meta-analyses of randomised trials. Direct comparison of different interventions in randomised trials and adjusted indirect comparison in which two interventions were compared through their relative effect versus a common comparator. The discrepancy between the direct and adjusted indirect comparison was measured by the difference between the two estimates. Database of abstracts of reviews of effectiveness (1994-8), the Cochrane database of systematic reviews, Medline, and references of retrieved articles. 44 published meta-analyses (from 28 systematic reviews) provided sufficient data. In most cases, results of adjusted indirect comparisons were not significantly different from those of direct comparisons. A significant discrepancy (P<0.05) was observed in three of the 44 comparisons between the direct and the adjusted indirect estimates. There was a moderate agreement between the statistical conclusions from the direct and adjusted indirect comparisons (kappa 0.51). The direction of discrepancy between the two estimates was inconsistent. Adjusted indirect comparisons usually but not always agree with the results of head to head randomised trials. When there is no or insufficient direct evidence from randomised trials, the adjusted indirect comparison may provide useful or supplementary information on the relative efficacy of competing interventions. The validity of the adjusted indirect comparisons depends on the internal validity and similarity of the included trials.
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                Author and article information

                Contributors
                Journal
                Neurology
                Neurology
                Ovid Technologies (Wolters Kluwer Health)
                0028-3878
                1526-632X
                October 28 2019
                October 29 2019
                October 29 2019
                October 07 2019
                : 93
                : 18
                : 793-809
                Article
                10.1212/WNL.0000000000008319
                31591277
                441ff9f5-eb92-4303-9b77-5427533bc956
                © 2019
                History

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