The evidentiary standards for the approval of drugs to treat human disease are set forth in the relevant sections of the Food, Drug, and Cosmetic Act. This chapter focuses on some of the more important and current issues related to the demonstration of effectiveness of drugs and biologics. In essentially all cases, drugs to treat neurological disease are approved on the basis of clinical trials that examine the drug's effects on a face valid measurement with clinical meaning. The FDA defines orphan diseases as those with a prevalence of less than 200000 in the US. In the case of a trial designed to establish the superior safety profile of one drug compared to another, it is also critical that the trials examine a full range of adverse events, and employ methods sensitive enough to adequately assess them.