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Disability as an outcome in MS clinical trials

From the University of Oxford Department of Clinical Neurology (G.C.E.), John Radcliffe Hospital, Oxford, UK; Sylvia Lawry Centre for Multiple Sclerosis Research (L.H., M.D., C.L.), Munich, Germany; and The Department of Neurology (J.H.N.), the Mayo Clinic College of Medicine, Rochester, MN.

Address correspondence and reprint requests to Professor George C. Ebers, University of Oxford Department of Clinical Neurology, Level 3, West Wing, John Radcliffe Hospital, Oxford OX3 9DU, UK george.ebers{at}clneuro.ox.ac.uk

Background: Inferences about long-term effects of therapies in multiple sclerosis (MS) have been based on surrogate markers studied in short-term trials. Preventing progressive disability is the key therapeutic goal but there remains no validated definition for its measurement in a trial context. Meanwhile, MS trials continue to shorten and to depend on unvalidated surrogates. Since there have been no treatment claims for improving unremitting disability, worsening of disability in the placebo/control arm must occur for effectiveness on this outcome to be shown.

Methods: We examined widely-used clinical surrogates of long-term disability progression in individual patients with MS within a unique database from the placebo arms of 31 randomized clinical trials.

Results: Detection of treatment effects in secondary progressive MS trials is undermined by noise in disability measurement. Whereas existing measures can be partially validated in secondary progressive MS, this is not the case in relapsing-remitting MS. Here, examination of widely used definitions of treatment failure demonstrated that disability progression was no more likely than similarly defined improvement. Existing definitions of disease progression in short-term intervention trials in relapsing-remitting patients reflect random variation, measurement error, and remitting relapses.

Conclusion: Clinical surrogates of unremitting disability used in trials of relapsing-remitting multiple sclerosis cannot be validated. Trials have been too short or degrees of disability change too small to measure the key outcomes. These analyses highlight the difficulty in determining effectiveness of therapy in chronic diseases.

Abbreviations: EDSS = Expanded Disability Status Scale; MS = multiple sclerosis; RCTs = randomized clinical trials; RRMS = relapsing remitting MS; SLC = Sylvia Lawry Centre for Multiple Sclerosis Research; SPMS = secondary progressive MS.

Supplemental data at www.neurology.org

Editorial, page 620

e-Pub ahead of print on May 14, 2008, at www.neurology.org.

Ludwig Heigenhauser is funded by the SFB 386 of the German Science Foundation DFG. The SLC acknowledges the role played by the Porticus and Hertie Foundations in providing financial support at a critical time enabling the completion of these studies.

Disclosure: The Sylvia Lawry Centre was established so that data analysis independent of trial sponsors could be carried out.29 The authors report no disclosures.

Received October 26, 2007. Accepted in final form February 4, 2008.

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