The National Institute on Alcohol Abuse and Alcoholism (NIAAA) requires enhanced monitoring and reporting for NIAAA-supported clinical trials that are rated as greater than minimal risk (as defined in federal regulations at 45 CFR 46.102(i) and 21 CFR 50.3(k)). The purpose of this guidance document is to clarify risk level definitions and NIAAA’s monitoring and reporting expectations for all NIAAA-funded clinical trials.

The NIAAA Program Officer (PO) will assess the risk level, proposed level of monitoring, and reporting frequency and requirements for each clinical trial assigned. The level of monitoring and reporting should be commensurate with the level of risk.

In all cases, the Principal Investigator (PI) and the Institutional Review Board (IRB) retain their monitoring and oversight responsibilities for the study regardless of any additional monitoring requirements that may be added (e.g., a Data and Safety Monitoring Board). All requirements specified here are in “addition to” and not “in lieu of” the PI and IRB monitoring and oversight responsibilities.

Risk Levels:

LOW RISK means no greater than minimal risk to clinical trial participants. This means that the probability and magnitude of harm or discomfort anticipated in the research are not greater than those ordinarily encountered in daily life or during the performance of routine physical and psychological examinations or tests and that confidentiality is adequately protected. This category includes protocols that pose “no greater than minimal risk” according to federal regulations.

LOW RISK: Requires ongoing monitoring by the PI and IRB – reporting frequency at least annually to NIAAA.

MEDIUM RISK means greater, but not significantly greater than minimal risk to clinical trial participants. This means that the probability and magnitude of harm or discomfort anticipated in the research risks are more than minimal risk, but not significantly greater. Studies that fall under this category will range in their probability of a moderate-severity event occurring as a result of study participation (and the level of safety monitoring will depend on that probability) but there are adequate surveillance and protections in place to identify adverse events promptly and to minimize harm.

MEDIUM RISK: Requires ongoing monitoring by the PI and IRB and may also require monitoring by an Independent Safety Monitor or an independent Data and Safety Monitoring Board (DSMB) – reporting frequency at least every 6 months (unless otherwise noted in Notice of Award) to NIAAA.

HIGH RISK means significantly greater than minimal risk to clinical trial participants. This means that the probability of an event that is serious, prolonged and/or permanent occurring as a result of study participation or there is significant uncertainty about the nature or likelihood of adverse events. Trials with Significantly Greater than Minimal Risk require adequate protections for foreseeable adverse events.

HIGH RISK: Requires ongoing monitoring by the Principal Investigator, IRB, and a DSMB (or equivalent) – reporting frequency at least every 3 months (unless otherwise noted in Notice of Award) to NIAAA.

Monitoring Recommendations Based on Level of Risk:

Safety monitoring for a protocol must be appropriate for the level of risk identified (e.g., Low, Medium, or High). A combination of factors used in assessing the level of risk drives the intensity of monitoring required for a protocol. The requirements outlined below represent the minimal necessary to ensure subject safety. In some cases, the NIAAA PO may require more frequent and/or enhanced monitoring. Additionally, changes to the research project during the course of a study may necessitate an increased level of monitoring (see NIH Guidance NOT-OD-12-129).

Regardless of the level of risk, the PI (or approved co-investigator) will monitor the study with prompt reporting of serious adverse events (SAE) or unanticipated problems and other study related information to the IRB, NIAAA, and other agencies as required. For all clinical trials, it is expected that team meetings between the PI and his/her staff will be conducted on a routine basis to discuss any new adverse events or changes in the protocol. A Data and Safety Monitoring Plan (DSMP) that addresses the potential risks, reporting requirements of adverse events, and elements set-forth by NIAAA will be reviewed and approved by the NIAAA Program Officer. Please refer to the NIAAA DSMP requirements for NIAAA expectations and DSMP elements. This plan will be revised and updated in concurrence with protocol changes that affect risk.

Standard reporting of unanticipated problems and serious adverse events to the IRB is required regardless of the level of monitoring.

Low Risk Studies – Standard monitoring requirements and reporting frequencies.

Medium Risk Studies - Non-serious adverse events and unrelated serious adverse events will be reported in the progress report at the frequency determined by the Program Officer’s risk assessment but at least annually. In addition, for clinical trials falling into this risk category, the IRB-approved clinical protocols will be reviewed by the NIAAA Program Officer for completeness and consistency with the grant application. For all Medium Risk (greater than minimal risk) studies, sufficient surveillance and protections must be in place to adequately identify adverse events promptly. An Independent Safety Monitor should monitor the clinical trials when the Principal Investigator is blinded to treatment arms. An Independent Safety Monitor or independent DSMB may also be utilized for the studies/trials that have a higher probability of a moderate-severity event occurring, to review adverse events as they occur and make recommendations as they deem necessary to the study team.

High Risk Studies - Non-serious adverse events and unrelated serious adverse events will be reported in the progress report at the frequency determined by the Program Officer’s risk assessment but at least annually. In addition, for clinical trials falling into this risk category, the IRB-approved clinical protocols will be reviewed by the NIAAA Program Officer for completeness and consistency with the grant application. For all High Risk (significantly greater than minimal risk) studies, sufficient surveillance and protections must be in place to adequately identify adverse events promptly. An Independent Safety Monitor should monitor the clinical trials when the Principal Investigator is blinded to treatment arms. An independent DSMB is required and must be utilized for all studies rated as High Risk.

For questions or comments, please contact:

Megan Ryan
Clinical Trial Operations and Technology Innovation Officer
Office of the Director/NIAAA
(email) mryan1@mail.nih.gov