Regulatory glossary

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 rule is short and the deadlines are unforgiving. Most of the difficulty is not the clock, it 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, hospitalisation or prolongation of hospitalisation, 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.

That last term is where sponsors diverge. "Reasonable possibility" is a causality judgement, 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, not from the event, not from the investigator's assessment, and not from your own causality meeting. Sponsors lose days to internal triage that the regulation does not allow for.

What else is reportable

Expedited reporting is not limited to 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 the ones missed most often, because they require somebody to be looking across the study rather than at one case at a time.

Who else has to be told

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 treat the format work as a project with its own lead time, not a formatting step at the end.