Sponsor notifications to FDA and all participating investigators (i.e., all investigators to whom the sponsor is providing a drug under its or investigators' INDs) which may include:

1. Serious and unexpected suspected adverse reaction;
2. A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure;
3. One or more occurrences of an event that is not commonly associated with drug exposure, but is otherwise uncommon in the population exposed to the drug;
4. An aggregate analysis of specific events observed in a clinical trial that indicates those events occur more frequently in the drug treatment group than in a concurrent or historical control group;
5. Findings from other studies that suggest a significant risk in humans exposed to the drug;
6. Findings from animal or in vitro testing that suggest a significant risk in humans exposed to the drug; or
7. A clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.