Outcome Measures in Relapsing-Remitting Multiple Sclerosis: Capturing Disability and Disease Progression in Clinical Trials

Figure 1

Clinical outcome measures and surrogate endpoints in Phase 3 clinical trials.

(a) Primary outcome measures for clinical trials are carefully selected. Clinically relevant outcomes that directly impact the patient are ideal for Phase 3 clinical trials. In MS trials, disability (as measured by the Expanded Disability Status Scale), disease progression (such as the conversion to clinically definite MS), and annualized relapse rate are commonly chosen as the primary endpoint

(b) Ideal relationship (solid lines) between an exposure and outcome, through a surrogate endpoint. The intervention does not affect the outcome without impacting the surrogate. A surrogate may fail if it has other effects on the outcome not mediated by the surrogate (dotted line) or the intervention only impacts the pathway involving the surrogate, and other causal mechanisms exist (dashed line)

(c) While imaging has played a significant role in the diagnosis and prognosis for MS patients, MRI metrics have not been accepted as surrogates for Phase 3 clinical trials. For a surrogate to be valid, the effects of the intervention must be entirely mediated through the surrogate. Imaging surrogates are not sufficient to explain the complex pathophysiology resulting in disability, disease progression, and clinical relapses in MS