How do we define progression in clinical trials?

Epub: Healy et al. Assessment of definitions of sustained disease progression in relapsing-remitting multiple sclerosis. Mult Scler Int. 2013;2013:189624. doi: 10.1155/2013/189624. Epub 2013 Mar

Sustained progression on the expanded disability status scale (EDSS) is a common outcome measure of disease progression in clinical studies of MS. Unfortunately, this outcome may not accurately measure long-term and irreversible disease progression. To assess the performance of definitions of sustained progression, patients with relapsing-remitting MS (RRMS) or a clinically isolated syndrome with evidence of lesions on a brain MRI were included in our study. Fifteen definitions of sustained progression using both the EDSS and the functional system (FS) scales were investigated. The impact of both relapses and changes in provider on the probability of maintaining progression was also evaluated. Although the provider scoring the EDSS sometimes changed during follow up, the provider had access to previous EDSS scores. Between 15.8% and 42.2% of patients experienced sustained progression based on the definitions using EDSS as the outcome, but nearly 50% of these patients failed to maintain sustained progression for the duration of followup. When FS scales were used, progression was most common on the pyramidal and sensory scales. Unfortunately, progression on specific FS scales failed to be more sensitive to irreversible disability. Relapses or changes in provider did not explain the poor performance of the measures. Short-term changes in the EDSS or FS scores may not be an accurate marker of irreversible change in RRMS.

Apologies for the radio silence recently – I have been somewhat preoccupied by training for the London Marathon!

This study looks at something that is really important in clinical trials, but is often overlooked. One of the commonly used outcome measures in clinical trials in RRMS is “time to sustained disability progression”, as a marker of people developing secondary progressive disease. Commonly used measures of this include an increase in the EDSS of 1 or 1.5 points, which is still present at a second assessment, often 3 months later. The assessment at 3 months is an attempt to differentiate progression from EDSS increases seen in the context of relapses.

The authors of this study looked at longer term outcomes in almost 1000 patients who were being reviewed at their clinic (i.e. not in the context of clinical trials). Patients were followed up every 6 months, and whilst the EDSS was not always performed by the same person, there was access to previous EDSS Scores. The abstract says it all really – half of those who met various criteria for “sustained progression” and therefore would potentially have met the endpoint in clinical trials, later had an improvement in EDSS (i.e. the increase in disability was not truly sustained). The explanations for this include relapses and inter-rater variability. This study confirms something that I have been worried about for some time. The definition for progressive disease in RRMS trials is flawed; an EDSS increase at 3 months can clearly be due to prolonged recovery from relapse. So how do we overcome this? I don’t have the answer to that, but it seems that the EDSS may not be the be-all and end-all in outcome measures. 

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