Disability as an outcome in MS clinical trials

Area of Science:

• Neurology
• Clinical Trials
• Multiple Sclerosis Research

Background:

• Inferences on long-term multiple sclerosis (MS) treatment effects rely on surrogate markers from short-term trials.
• Preventing progressive disability is crucial, yet no validated measurement exists for MS trials.
• MS trials are shortening and increasingly depend on unvalidated surrogate markers.

Purpose of the Study:

• To examine widely-used clinical surrogates for long-term disability progression in individual MS patients.
• To assess the validity of surrogate markers in the context of randomized clinical trials for MS.

Main Methods:

• Analysis of a unique database from placebo arms of 31 randomized clinical trials in MS.
• Examination of widely-used definitions of treatment failure and disability progression.

Main Results:

• Detection of treatment effects in secondary progressive MS trials is hindered by measurement noise.
• Existing disability measures show partial validation in secondary progressive MS but not in relapsing-remitting MS.
• Definitions of disease progression in short-term relapsing-remitting MS trials reflect random variation, measurement error, and relapses, not true progression.

Conclusions:

• Clinical surrogates for unremitting disability in relapsing-remitting MS trials lack validation.
• Trial durations and observed disability changes are often insufficient to measure key outcomes.
• Determining therapeutic effectiveness in chronic diseases like MS presents significant challenges.