The Expanded Disability Status Scale (EDSS) represents the most widely accepted measure of disease progression in multiple sclerosis (MS), and is used in many natural history studies. This chapter discusses natural history of relapsing onset MS, primary progressive MS, changes in natural history and impact on clinical trial design, traditional prognostic factors, and other factors which may influence prognosis such as race, comorbid diseases, and health behaviors. Pharmacoepidemiological studies using real world data derived from clinical practice represent a cost-effective means of evaluating the long-term effectiveness of immunomodulatory drug treatments for MS. Along with evidence from the basic sciences, epidemiological studies can provide insights into potentially novel treatments, as well as the rationale and hypotheses for testing these treatments in clinical trials. For example, vitamin D and estrogen are being evaluated in clinical trials based partly on epidemiological observations. Heterogeneity remains the hallmark of MS.

Relapsing remitting multiple sclerosis (RRMS) patients have periodic relapses occurring at variable rates, but generally less than one per year. The factor complicating MS clinical trials is disease heterogeneity, which is one of the hallmarks of MS. The annualized relapse rate or the number of relapses is the most common primary outcome measure for RRMS clinical trials. Relapses are subjective. As symptoms fluctuate, and are influenced by many factors- fever, high ambient temperature, anxiety, intercurrent illness, and sleep deprivation, among others - it is often not clear whether an individual MS patient has experienced a relapse or not. Also, the required duration beyond which symptoms must persist has not been standardized. There are no demonstrably effective therapies for primary neuroprotection, though it appears possible to slow the neurodegerative process in early-stage MS with immunomodulatory or immunosuppressive drugs. Presumably, this form of neuroprotection is secondary to the anti-inflammatory effect.

The imperative to develop more effective medication for multiple sclerosis (MS) persists. In view of the availability of several partially effective immunomodulatory drugs for the treatment of MS, the National MS society (NMSS) convened an international task force to deliberate the continued use of placebo-controlled trials. Clearly, patients should not be deprived of the opportunity to participate in a placebo-controlled trial if they do not wish to use approved therapies. The ethical issues and practical limitations governing placebo controlled trials remain complex. Clinical trialists clearly have a mandate to include ethical considerations in all aspects of the design, implementation, and conduct of clinical trials. The continued use of placebo controlled randomized clinical trials in an era of partially effective therapy remains controversial. Both the utility and ethical conduction of placebo-controlled trials in MS are likely to continue to evolve as the MS therapeutic armamentarium grows increasingly refined.