Ebers, C. G. Heigenhauser, Ludwig Daumer, Martin Lederer, C. Noseworthy, J. H.
Year of Publication:
Discussion paper // Sonderforschungsbereich 386 der Ludwig-Maximilians-Universität München 429
Background Inferences about long-term effects of therapies in multiple sclerosis (MS) have been based on surrogate markers studied in short-term trials. Nevertheless, MS trials have been getting steadily shorter despite the lack of a consensus definition for the most important clinical outcome - unremitting progression of disability. Methods We have examined widely used surrogate markers of disability progression in MS within a unique database of individual patient data from the placebo arms of 31 randomised clinical trials.Findings Definitions of treatment failure used in secondary progressive MS trials include much change unrelated to the target of unremitting disability. In relapsing-remitting MS, disability progression by treatment failure definitions was no more likely than similarly defined improvement for these disability surrogates. Existing definitions of disease progression in relapsing-remitting trials encompass random variation, measurement error and remitting relapses and appear not to measure unremitting disability. Interpretation Clinical surrogates of unremitting disability used in relapsing-remitting trials cannot be validated. Trials have been too short and/or degrees of disability change too small to evaluate unremitting disability outcomes. Important implications for trial design and reinterpretation of existing trial results have emerged long after regulatory approval and widespread use of therapies in MS, highlighting the necessity of having primary trial data in the public domain.