Time to sustained worsening in the expanded disability status scale (EDSS) as the standard for evaluating the accumulation of disability has been used as a measure of clinical efficacy in many relapsing-remitting multiple sclerosis (RRMS) clinical trials. However, this measurement usually requires a large sample and long-term study to demonstrate the treatment effect.
Annualized relapse rate or time to first relapse is also widely used as alternative measurements of clinical efficacy. A formal statistical validation of short-term relapse activity as a surrogate endpoint for long-term sustained progression of disability could potentially permit smaller, shorter, and less expensive clinical trials in RRMS. Four statistical validation/evaluation approaches consistently showed that relapse activity through one year of treatment serves as statistically valid surrogate endpoint for time to sustained progression of disability. The analysis demonstrates that long-term sustained progression of disability can be predicted by short-term relapse measures with 4 consistent validations of statistical approaches, including a formal statistical hypothesis test.
This was demonstrated in a large phase III trial of natalizumab and showed that the beneficial clinical effect of natalizumab on sustained progression of disability at 2 years in patients with RRMS can be predicted by the total number of relapses at 1 year.
CoI: This study was undertaken by Biogen.
“What this study shows is that events in the first 12 months of a clinical trial predict what is going to happen at the end of the study and possibly beyond. I am aware of data sets beyond this data that show the same thing. I think this is valid and may be it is time for the regulators (FDA and EMA) to accept short-term surrogates to help speed-up drug development. The problem with this approach it won’t allow sufficient data to be collected to make a judgement on safety.”