Unfortunately, there are a number of reasons that make progressive disease difficult to clinically study in a rigorous manner: 1. For one, there are poor animal models of progressive disease, which makes doing basic laboratory research challenging. Dr. Mueller in our lab is working on such an animal model. 2. It’s also very difficult to measure the worsening in progressive disease because there are no biomarkers for progression and our outcome measures are not very good. The outcomes in current MS medication trials use endpoints such as relapse rate and MRI changes, which are not useful measures in patients with progressive MS. The 'EDSS' is a widely used disability scale in MS trials, however there are numerous issues with this outcome measure as well. For example, from a middle range on in the scale, it is almost entirely dependent on walking ability (i.e. someone who uses a walker with 20/20 vision has the same EDSS as someone who is blind and also uses a walker.) 3. Also, in progressive disease disability accumulates over a very long period of time, on the order of 10 years or more. Any trial would have to be a very long (and therefore expensive) trial, which would dramatically affect the number of patients who remain in the study for its entire duration. 4. Particularly in primary progressive MS, there are fewer patients so trial recruitment is reduced. 5. Finally, although purely speculative, the ongoing pathology of progressive disease may be restricted to the brain and spinal cord so medications delivered to the entire body (which are bad at actually getting to the brain and spinal cord) may not be the best route of administration. This is one reason that the IMSMP is investigating intrathecal (directly into the spinal fluid) administration of certain medications.