Multiple sclerosis trial designs for the 21st century: building on recent lessons.

Starting with the first positive pilot study of glatiramer acetate, trial design in multiple sclerosis has advanced considerably over the past two decades, successively building and improving on previous successes in the implementation and analysis of new clinical trials. Most of these trials have been successful and this has led to the regulatory approval and commercial availability of six agents for the treatment of multiple sclerosis. During this period, outcome measures have been validated to determine the efficacy and safety of such agents, notably those useful in reducing the inflammatory aspects of disease. These include measurements of relapse reduction (annualized relapse rate, time to first relapse, proportion of subjects relapse free), disability (change in EDSS score, change in MSFC score) and MRI metrics (measurements of gadolinium-enhancing lesions, T1 and T2 lesion load). Recent trial design has shown that one can answer some clinical questions after one year on study and that these results may be predictive of more robust two-year trial data. The other important recent lesson involves emergence of rare complications of immunomodulatory therapy, namely progressive multifocal leucoencephalopathy with natalizumab that blocks the access of immune cells to the nervous system. In addition to the increased need for enhanced safety assessment, this issue will have an impact both on the study of combination therapies and on the use of combinations in clinical practice.