Introduction

Clinical trial investigators are responsible for reporting Serious Adverse Events (SAE), Unanticipated Problems (UPs), and other significant research-related events to the National Institute on Alcohol Abuse and Alcoholism (NIAAA) for all NIAAA-funded research. Reporting such events is necessary for NIAAA’s oversight and protection of the rights and welfare of participants in NIAAA-funded research. The following describes expectations and steps for reporting SAEs, including SAEs that are considered UPs, to NIAAA. Investigators are also responsible for reporting SAEs and UPs to other regulatory and administration groups (e.g., OHRP, FDA, local IRB, etc.) in addition to NIAAA. Unless otherwise stated in the Notice of Grant Award, summary non-serious adverse events should be reported during each reporting cycle. 

Background

In June of 1998, NIH issued a policy stating that each NIH Institute or Center (IC) "should have a system for the appropriate oversight and monitoring of the conduct of clinical trials to ensure the safety of participants and the validity and integrity of the data for all NIH-supported or conducted clinical trials." According to this policy, data and safety monitoring is required for all types of clinical trials, including physiologic, toxicity, and dose-finding studies (Phase I); efficacy studies including human laboratory studies (Phase II); efficacy, effectiveness, and comparative trials (Phase III); etc. It includes all types of intervention studies, whether medication or non-medication (e.g., behavioral, prevention, diagnostic) trials. To this end, all clinical trials are required to track and report adverse events (AEs), SAEs, and UPs.

Definitions

Adverse Event (AE): Any untoward or unfavorable medical occurrence in a human study participant, including an abnormal sign (e.g. abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participants' involvement in the research whether or not considered related to participation in the research. 

Serious Adverse Event (SAE): Defined by OHRP guidance as any adverse event temporally associated with the subject’s participation in research that meets any of the following criteria: 

1. Results in death;
2. Is life-threatening;
3. Requires inpatient hospitalization or prolongation of existing hospitalization;
4. Results in a persistent or significant disability/incapacity
5. Results in a congenital anomaly/birth defect;
6. Any other adverse event that may jeopardize the subject’s health and may require medical or surgical intervention to prevent one of the other outcomes listed in this definition.

Relatedness:  The event’s relationship to the study intervention and/or participation as assessed by the site manager. 

Unanticipated Problem (UP):  Defined by 45 CFR part 46 as any incident, experience, or outcome that meets all of the following criteria: 

1. unexpected (in terms or nature, severity, or frequency) given the research procedures described in protocol-related documents and the characteristics of the participant population being studies; AND
2. related or possibly related to participation in the clinical research; AND
3. suggests the research places participants or others at a greater risk of harm than was previously known or recognized. 

**The vast majority of adverse events are not unanticipated problems. Only a small proportion of adverse events are unanticipated problems. Unanticipated events can include other incidents experiences, and outcomes that are not adverse events. 

Policy

Consistent with NIH policy, the Clinical Investigator is responsible for the accurate documentation, investigation, and follow-up of adverse events occurring during a clinical trial.   

Procedures for identifying, monitoring, and reporting SAEs and UPs must be described in the study's Institutional Review Board (IRB) and NIAAA approved Data and Safety Monitoring Plan (DSMP) and the study protocol submitted to the NIAAA.  At a minimum, the procedures must include:

• Reporting all SAEs and UPs during the treatment and follow-up phases to NIAAA within 48 hours using the NIAAA SAE Reporting tool.
• For multi-center studies, procedures for notifying all participating study clinical investigators of events and resulting consequences in study procedures. 
• For all UPs, a corrective action plan and measures to prevent reoccurrence must be submitted to NIAAA subsequent or in parallel with the initial UP report. For UPs that are also SAEs, use the NIAAA SAE Reporting tool for reporting the event. 

Clinical Investigator Responsibilities

Investigators are responsible for completing initial SAE documentation as well as completing any follow-up or final SAE forms (if applicable). Reporting SAEs to NIAAA does not supplant reporting these events to other regulatory bodies such as local IRBs, FDA, OHRP, etc. in a timely manner. NIAAA requires Investigators to report SAEs to NIAAA using the NIAAA Serious Adverse Event Reporting tool.   

Determining if an Adverse Event is a Serious Adverse Event

All adverse events should be noted and considered important, but the SAE Reporting tool should only be used for prompt reporting of SAEs. Adverse events not considered an SAE, except for a non-serious UP, should be documented and reported to NIAAA during the appropriate reporting period (e.g., annual, quarterly, etc.). To assist in determining if an adverse event is an SAE, see the Adverse Event Decision Tree for Principal Investigators [PDF – 393 KB]. If further clarification is needed, investigators should consult their IRB of record and the NIAAA SAE Coordinator for additional guidance.  

Questions

For questions or comments please contact: NIAAASAEreports@mail.nih.gov.