IND Safety Report: The 7 and 15 Day Clocks

An IND safety report is the expedited notification a sponsor sends FDA when something in a study under an Investigational New Drug application meets the reporting standard in 21 CFR 312.32.

The deadlines are short, but most of the difficulty is deciding whether an event qualifies at all.

The three-part test

A suspected adverse reaction is reportable only if it is all three of the following. Failing any one of them takes it out of expedited reporting.

• Serious. It resulted in death, a life-threatening experience, hospitalization or prolongation of hospitalization, persistent or significant incapacity, or a congenital anomaly, or required intervention to prevent one of those outcomes.
• Unexpected. Not listed in the investigator brochure, or not listed at the observed specificity or severity. An event listed as mild that occurs as severe is unexpected.
• Suspected, meaning there is a reasonable possibility that the drug caused it.

Sponsors diverge most on the third criterion. "Reasonable possibility" is a causality judgment, and the 2010 final rule moved it deliberately toward evidence: a single case of an event with no other explanation may qualify, while a routine event in a sick population usually needs an aggregate signal rather than one report.

The clocks

7 calendar days for an unexpected fatal or life-threatening suspected adverse reaction. This is a notification, and it can be by telephone or fax as well as in writing.

15 calendar days for any other suspected adverse reaction that is both serious and unexpected.

Both run from the sponsor's initial receipt of the information. The event date, the investigator's assessment and your own causality meeting do not reset the clock, and sponsors lose days to internal triage the regulation does not allow for.

Reportable findings beyond individual cases

• Findings from other studies, including animal or in vitro findings, that suggest a significant human risk.
• Aggregate analyses, where the sponsor determines events occur more frequently in the drug arm than in control.
• Increased rate of occurrence of serious suspected adverse reactions over the rate listed in the protocol or investigator brochure.

These are missed most often, because someone has to be looking across the study rather than at one case at a time.

Notifying investigators

The sponsor notifies FDA and all participating investigators. The investigator obligation is easy to overlook when a CRO handles the FDA submission, and it is the sponsor's obligation regardless of who performs it.

Format

FDA requires IND safety reports to be submitted electronically in E2B format to the FAERS database, with the agency's technical conformance guide setting out the details. Sponsors moving from paper or from a partner's system should plan the format work as a project with its own lead time.