Disability as an outcome in MS clinical trials
- 26 August 2008
- journal article
- Published by Wolters Kluwer Health in Neurology
- Vol. 71 (9), 624-631
- https://doi.org/10.1212/01.wnl.0000313034.46883.16
Abstract
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.Keywords
This publication has 28 references indexed in Scilit:
- Fast track to MS drugNature Biotechnology, 2004
- Assessment of different treatment failure criteria in a cohort of relapsing–remitting multiple sclerosis patients treated with interferon β: Implications for clinical trialsAnnals of Neurology, 2002
- Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 yearsMultiple Sclerosis Journal, 2000
- Disability outcome measures in therapeutic trials of relapsing-remitting multiple sclerosis: effects of heterogeneity of disease course in placebo cohortsJournal of Neurology, Neurosurgery & Psychiatry, 2000
- The natural history of multiple sclerosis:a geographically based studyBrain, 1999
- Genetics of Multiple SclerosisSeminars in Neurology, 1998
- Recommendations from the national multiple sclerosis society clinical outcomes assessment task forceAnnals of Neurology, 1997
- Intramuscular interferon beta‐1a for disease progression in relapsing multiple sclerosisAnnals of Neurology, 1996
- Copolymer 1 reduces relapse rate and improves disability in relapsing‐remitting multiple sclerosisNeurology, 1995
- Rating neurologic impairment in multiple sclerosisNeurology, 1983