Adverse Event (AE)

An adverse event is any undesirable, unexpected medical symptom or finding that a study subject experiences while taking a study medication or using a study device. Causality, or the relationship between cause and effect (study medication or device and medical occurrence), is generally not implied. For example, adverse events include such diverse circumstances as headaches, colds, vomiting, or motor vehicle accidents. The term adverse drug reaction (ADR) more accurately implies that a particular drug caused an untoward event. The database of adverse reactions to marketed products is known as AERS (Adverse Event Reporting System).

Adverse events can be categorized as either serious or nonserious. A serious adverse event is one that is fatal or life threatening, results in hospitalization or prolongs hospitalization, is significantly disabling or incapacitating, or is a congenital anomaly or birth defect. The FDA GCP guidelines include overdose as a serious adverse event.

All adverse events, serious and nonserious, must be recorded in source documents and case report forms. The investigator must immediately report all serious adverse events to the sponsor. The sponsor is then obligated to expedite the dissemination of this information to all concerned investigators, institutions, institutional review boards or institutional ethics committees (IRBs or IECs), and regulatory authorities. The term unexpected adverse event is used when the nature or severity of the event is inconsistent with product labeling (as detailed in the investigator brochure for an approved experimental drug or device) or the data sheet (package insert for a marketed product).

A grading system should be applied to the relationship of an adverse event to the study medication or device. Although regulatory documents do not specify this grading system, the following suggested system illustrates the intent of such a system:

• None: AE is definitely not associated with study drug or device.
• Remote: AE is not likely associated with study drug or device.
• Possible: There is a reasonable causal relationship between event and study drug or device, but AE could have been caused by participant's clinical state or other therapies participant has received.
• Probable: There is a reasonable causal relationship between event and study drug or device, event subsides when study item is discontinued, and event cannot be explained by study subject's usual clinical state.
• Highly Probable: There is a reasonable causal relationship between event and study drug or device, event subsides when study item is discontinued, and event reappears with repeat exposure to study drug or device.

The intensity and severity of the adverse event should also be graded on a scaled system. As with the grading of[Page 11] the causal relationship between a study drug or device and adverse event, there is no standard as to how to grade severity. The following suggested system illustrates the intent of such a system:

• Mild: AE is transient, does not require medical treatment, and does not interfere with subject's daily routine.
• Moderate: AE produces minor discomforts and concerns that may slightly interfere with subject's daily routine but are relieved with simple therapeutic measures.
• Severe: AE interrupts the subject's daily routine and requires systematic medical treatment.