Table 3 . Sample decision tree for expedited reporting of type C events.

Analysis of Category C events Based on observing increased frequency relative to control
Is imbalance clear? • Does a one-sided 80% confidence interval of the difference between observed and control (perhaps using meta-analysis of all related completed and ongoing studies) include 0? (or does the 80% confidence interval for a relative metric include 1?) • Is the relative risk compared to control less than 2? (For studies without controls, the risk is relative to expectation in a relevant historical population; for studies with controls, the risk is relative to the controls or to the historical population, or both.) • Does lumping similar events make the signal disappear? If the answers to all three are “yes,” the data do not show sufficient evidence of imbalance to file a 15-day report. If the answers to all three are “no,” the evidence of causality is clear enough to file a 15-day report. Otherwise, the increase is unclear.
No increase	Unclear increase	Clear increase
DO NOT SEND 15-DAY REPORT	CONSIDER SENDING 15-DAY REPORT IF	SEND 15-DAY REPORT
	Other safety outcomes (e.g., adverse events and laboratory data) support causality. OR The mechanism of action supports causality. OR
	Information could influence: • The way investigators manage patients • A patient's willingness to participate in the study. • Patients outside the trial OR Pooling similar endpoints strengthens signal. OR
	Event is potentially fatal or disabling. OR
	Otherwise, do not report but reanalyze as new events occur.

NOTE: This is a sample table. For a given drug, disease, or event, the sponsor might select a different confidence interval (i.e., not 80%) or a different relative risk (i.e., not 2).