Adverse Events: Introduction and FDA Reporting Requirements for IND studies

What are Adverse Events?
Adverse event means any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. An adverse event (also referred to as an adverse experience) can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, and does not imply any judgment about causality. 



An adverse event can arise with any use of the drug (e.g., off-label use, use in combination with another drug) and with any route of administration, formulation, or dose, including an overdose. 

What is a suspected adverse reaction? 
An adverse reaction means any adverse event caused by a drug. Adverse reactions are a subset of all suspected adverse reactions where there is reason to conclude that the drug caused the event. 

What is a suspected adverse reaction?
Suspected adverse reaction means any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable possibility’ means there is evidence to suggest a causal relationship between the drug and the adverse event. 


What is an unexpected adverse reaction?
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the investigator 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 current application, as amended. 

What are the serious adverse events? 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the investigator or sponsor, it results in any of the following outcomes: 
  • Death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital anomaly/birth defect.
  • Life-Threatening: An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have caused death. 

Safety Reporting Requirements 21 CFR 312.32(b))
The sponsor is required to review promptly all information relevant to the safety of the drug (21 CFR 312.32(b)). During the course of drug development, adverse event information is generally reported to a sponsor by investigators conducting clinical trials; however, a sponsor may become aware of new safety information from a variety of sources, both domestic and foreign. Some examples of sources are listed as follows, but safety information from any other source would also need to be reviewed and evaluated by the sponsor. 
 Animal studies or in vitro studies 
 Clinical or epidemiological investigations 
 Reports in the scientific literature
 Unpublished scientific papers 
 Information presented at scientific meetings 
 Reports from foreign regulatory authorities 
 Reports from commercial marketing experience
 Safety information presented at a professional meeting 
 Foreign spontaneous reports

Serious and Unexpected Suspected Adverse Reaction (21 CFR 312.32(c)(1)(i))
The sponsor must report in an IND safety report any suspected adverse reaction to study treatment (i.e., including active comparators) that is both serious and unexpected (21 CFR 312.32(c)(1)(i)).

To assist sponsors with determining whether an adverse event meets the definition of the suspected adverse reaction, the requirement under 21 CFR 312.32(c)(1)(i) specifies that sponsors are to report to FDA only if there is evidence to suggest a causal relationship between the drug and the adverse event and it provides examples of such evidence,
  • Individual Occurrences (21 CFR 312.32(c)(1)(i)(A))
  • One or More Occurrences (21 CFR 312.32(c)(1)(i)(B))
  • Aggregate Analysis of Specific Events (21 CFR 312.32(c)(1)(i)(C))
Where and How to Submit the Adverse Event Safety Reports
  • The report must be transmitted to the CDER or CBER review division that has responsibility for review of the IND (21 CFR 312.32(c)(1)(v)). IND safety reports should be submitted to all of the sponsor’s INDs under which the drug is being administered.
  • Reporting Time Frame The time frame for submitting an IND safety report to FDA and all participating investigators is no later than 15 calendar days after the sponsor determines that the suspected adverse reaction or other information qualifies for reporting (21 CFR 312.32(c)(1)).

For details visit: https://www.fda.gov/media/79394/download

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