Guidance to NCCIH Investigators on Reporting Serious Adverse Events and/or Unanticipated Problems in NCCIH-Funded Clinical Studies

Revised November 8, 2023

During the course of study conduct, serious adverse events* (SAEs) and/or unanticipated problems** (UPs) may occur and should be recorded and reported to NCCIH, the Institutional Review Board (IRB) of record, and the Independent Monitoring entity according to the timelines outlined in the NCCIH-approved Data and Safety Monitoring Plan (DSMP). 

NCCIH program directors will collect appropriate documentation and resolve outstanding queries when notified of an SAE and/or UP within an NCCIH-funded study. 

The following checklist outlines the submission of required information when notifying NCCIH.

CHECKLIST: (Required Submission to the NCCIH Program Director)

• SAE Report (formal report, not an email narrative) sent to IRB of record. If the study did not record the SAE on an institutional SAE Report Form, a sample SAE form can be found in the NCCIH Clinical Research Toolbox. The submitted SAE form should contain a written narrative of the SAE, including a timeline of event occurrence and follow-up actions taken. 
• Confirmation that the SAE reporting occurred according to the timelines outlined in the NCCIH-approved DSMP. Provide the date when the IRB of record was notified of the event. If the reporting deviated from the NCCIH-approved DSMP, include a written explanation.
• Correspondence from the IRB regarding SAE next steps/actions (for Related or Possibly Related SAEs).
• Correspondence from either the Medical Monitor, the Independent Monitoring Committee, or the Data and Safety Monitoring Board (as described in the approved DSMP) regarding SAE next steps/actions (for Related or Possibly Related SAEs).
• If the SAE is also a UP, please include any correspondence between the institution/IRB and documentation from the local IRB reporting the UP to the HHS Office of Human Research Protection (OHRP).
• If formal changes to the NCCIH-approved study documents are also being requested, please submit a copy of the track-changed study documents. If it is a Routine Oversight Study, NCCIH may request the study protocol and the informed consent document. 

NCCIH will review the document submission and request additional information as warranted.  

*A serious adverse event (SAE) is one that meets one or more of the following criteria:

• Results in death
• Is life-threatening (places the subject at immediate risk of death from the event as it occurred)
• Results in inpatient hospitalization or prolongs existing hospitalization
• Results in a persistent or significant disability or incapacity
• Results in a congenital anomaly or birth defect

An important medical event that may not result in death, be life threatening, or require hospitalization may be considered an SAE when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

**An unanticipated problem is one that meets the following criteria: 

The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to subjects or others to include, in general, any incident, experience, or outcome that meets all of the following criteria:

• Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are described in the protocol-related documents, such as the IRB-approved research protocol and informed consent document; and (b) the characteristics of the subject population being studied;
• Related or possibly related to participation in the research (“possibly related” means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and
• Suggests that the research places subjects or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.