Rare adverse events in clinical trials: understanding the rule of three

Investigators should report rare and very rare adverse events in clinical trials. Even though they may not give a signal in any single trial, a meta-analysis could reveal potentially important drug–adverse event associations that might require further verification. Data from a meta-analysis of such rare events can shorten the time to decision-making by regulatory agencies and/or drug manufacturers, especially in cases where the reported harms are severe. The benefit-harm profiles of new medicines are usually not fully known at the time of regulatory approval. …