Simon, R. “Optimal Two-Stage Designs for Phase II Clinical Trials,” Controlled Clinical Trials, 1989, Volume 10, pages 1-10. i The term “life -threatening” in the definition of “serious” refers to an event in which the patient is at risk of death at the time of the event; it does not refer to an event, which hypothetically might have caused death if it were more severe. ii Medically important conditions that may not result in death, be life- threatening or require hospitalization may be considered as SAE when, based upon appropriate medical judgment, they may jeopardize the patient or may require intervention to prevent one of the outcomes listed in the definition above. Examples of such events are intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or development of drug dependency or drug abuse. N.B.: The term “severe” is often used to describe the intensity (severity) of an event (such as: mild, moderate, or severe e.g., pain). The event itself may be of relatively minor medical significance (such as severe headache). This is not the same as “serious”, which is based on patient/event outcome or action criteria usually associated with events that pose a threat to patient’s life or vital functions. Seriousness (not severity) serves as a guide for defining regulatory reporting obligations.