US-FDA – IND Safety Reporting requirements

IND Safety Reporting Summary:

IND application sponsors are required to notify FDA in a written safety report of:

• any adverse experience associated with the use of the drug that is both serious and unexpected or
• any findings from tests in laboratory animals that suggest a significant risk for human subjects including reports of mutagenicity, teratogenicity, and carcinogenicity. 
• Findings from other studies
• Increased rate of occurrence of serioussuspected adverse reactions

Safety Reporting Regulations:

The IND safety reporting regulations distinguish between circumstances in which it is appropriate to submit IND safety reports based on individual cases and circumstances in which an IND safety report would need to be based on an aggregate analysis of SAEs to determine whether the events occur more frequently in the drug treatment group.

• The sponsor must report in an IND safety report any suspected adverse reaction to study treatment (including active comparators) that is both serious and unexpected. Before submitting an IND safety report, the sponsor needs to ensure that the event meets three criteria:
  • it is serious;
  • it is unexpected (i.e., not listed in the investigator’s brochure or is not listed at the specificity or severity that has been observed), or, if an investigator brochure is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the IND;
  • there is evidence to suggest a causal relationship between the drug and the adverse event (i.e., it is a suspected adverse reaction). If the adverse event does not meet all three criteria, it should not be submitted as an IND safety report.

Reporting is required only if there is evidence to suggest a causal relationship between the drug and the AE, such as:

• A single occurrence of an event that is uncommon and known to be strongly associated with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome).
• 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 (e.g., tendon rupture).
• An aggregate analysis of specific events observed in a clinical trial, indicating that they occur more frequently in the drug treatment group than in a concurrent or historical control group. Such events may be known consequences of the underlying disease or condition or events that commonly occur in the study population independent of drug therapy. Such events could also be related to an intervention or therapy that is standard of care for the disease (e.g., background treatment).

• The reporting is not required for events which the investigator’s assessment is positive for causality but the sponsor’s evaluation did not find evidence to suggest a causal relationship between the drug and the event.

• The reporting is must for events which the investigator’s assessment is negative for causality but the sponsor’s evaluation found evidence to suggest a causal relationship between the drug and the event

• The study endpoints, including unblinded study endpoints, are not ordinarily reported in IND safety reports, except when there is evidence of a causal relationship between the drug and the event

• Findings from clinical, epidemiological, or pooled analysis of multiple studies are required to be submitted. Reports are required for studies from any source, regardless of whether they are conducted under the IND or by the sponsor

• Sponsor must report any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or investigator brochure.

Analysis of Similar Reports

This analysis, required for 15 day expedited reports, should be based on information from all other INDs held by the sponsor and any other relevant information known to the sponsor. In addition, the suspected AR should be examined in the context of other related AEs including those in placebos, comparators and those in pre- and post-marketing studies.

Reporting Timelines:

• Unexpected serious suspected adverse reactions and observations from animal studies suggesting significant risk to human subjects must be reported to FDA as soon as possible but no later than within 15 calendar days following the sponsor’s initial receipt of the information.Unexpected fatal or life-threatening suspected adverse reactions represent especially important safety information and must be reported to FDA as soon as possible but no later than 7 calendar days following the sponsor’s initial receipt of the information.
• Follow-up reporting: Any relevant additional information obtained by the sponsor that pertains to a previously submitted IND safety report must be submitted as a Follow-up IND Safety Report. Such report should be submitted without delay, as soon as the information is available but no later than 15 calendar days after the sponsor receives the information.

References:

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/sponsor-responsibilities-safety-reporting-requirements-and-safety-assessment-ind-and

https://www.fda.gov/drugs/investigational-new-drug-ind-application/ind-application-reporting-safety-reports

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.32