NIMH Guidance on Risk-Based Monitoring

The National Institute of Mental Health (NIMH) requires enhanced monitoring for NIMH-supported human subjects research that is more 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 the NIMH’s monitoring expectations to mitigate those risks.

The NIMH expects applicants and offerors to weigh the foreseeable risks and anticipated benefits to participating in research (45 CFR 46.111(a)(2) ) when applying for NIMH research support. Various factors are taken into consideration when assessing the nature, likelihood and acceptability of the risks of harm. The criteria and examples for each category are described below. Additional factors may include: the potential for the invasion of privacy/breach of confidentiality, psychological effects or social implications of the study, and the potential for conflicts of interest.

Some studies may not neatly fit into one specific category but instead have elements of two or more categories (e.g., a routine intervention in an actively psychotic participant). In such instances, the level of monitoring required by the higher of the two associated risk categories should be selected. The NIMH Program Officer will assess the risk level and proposed level of monitoring in the application (and may consult with the NIMH Office of Clinical Research (OCR) as needed). The level of monitoring should be commensurate with the level of risk, and the monitoring plan should be established (and approved by the NIMH) prior to initiating study recruitment. In all cases, the principal investigator and the Institutional Review Board 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).

Minimal Risk: Requires ongoing monitoring by the Principal Investigator (PI) and Institutional Review Board (IRB)
Minimal Risk to subjects 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.

Examples of Minimal Risk are:

• Study poses no more risk than expected in daily life (e.g., blood draw, physical exam, routine psychological testing).
• Non-interventional studies (e.g., observational studies of behavior or nutrition).
• Survey/Questionnaire studies of a non-sensitive nature.
• Electrophysiological studies in healthy subjects or clinical populations (surface recordings such as EEG , ERP, MEG )
• Genomic studies
• Non-invasive imaging (e.g., MRI  and fMRI ) in healthy subjects or clinical populations to investigate basic mechanisms of brain function.
• Research involving the collection or meta-analysis of existing data, documents, records, pathological specimens, or diagnostic specimens to understand basic bio-behavioral processes.

Greater than Minimal Risk: Requires ongoing monitoring by the Principal Investigator and IRB and may also require monitoring by an Independent Safety Monitor or an independent Data and Safety Monitoring Board

Greater than Minimal Risk to subjects 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.

Examples of Greater than Minimal Risk:
Monitored by the Principal Investigator and IRB:

• Some imaging studies (e.g. PET scan )
• Studies using transcranial magnetic stimulation
• Post-approval studies of FDA-approved drugs or devices  (may require an independent safety monitor if the PI is blinded to randomization)

Monitored by an Independent Safety Monitor (in addition to the PI and IRB):

• Studies involving treatment delays or medication washouts or placebo controlled studies in clinical populations
• Subjects with serious mental illness in a treatment study (may require an independent DSMB)
• Some first-in-human or Phase I investigational intervention (may require an independent DSMB based on preclinical findings)

Monitored by an independent Data and Safety Monitoring Board (in addition to the PI and IRB):

• Phase II Investigational New Drug (IND) /Investigational Device Exemption (IDE)  studies
• Phase III studies 
• Some first-in-human or Phase I investigational intervention (may require an independent DSMB based on preclinical findings) (http://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdf )
• Multi-site clinical trial  (independent DSMB required per NIH policy )

Significantly Greater than Minimal Risk: Requires ongoing monitoring by the Principal Investigator, IRB, and the NIMH-constituted Data and Safety Monitoring Board
Significantly Greater than Minimal Risk to subjects means that there is a 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.
Examples of Significantly Greater than Minimal Risk:

• Interventions to prevent or treat serious conditions (e.g., conditions associated with early death, significant self-harm, or danger to others)
• Involves an intervention or invasive procedure with substantial risk or high potential for serious adverse events (e.g., an investigational agent with high liability for toxicity)
• Clinical trials to support the testing of investigational implantable devices
• Some clinical trials involving vulnerable populations (e.g., children, pregnant women, prisoners etc.)
• Some studies of new chemical entities or drugs for which there is limited or no available safety data in humans (see FDA guidance http://www.fda.gov/downloads/Drugs/Guidances/UCM078932.pdf  )

Monitoring Recommendations Based on Level of Risk:
Safety monitoring for a protocol must be appropriate for the level of risk identified. 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 NIMH OCR or the PO may require more frequent and/or enhanced monitoring along with site initiation visits and regular monitoring visits by the NIMH. 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 ).

Standard reporting of unanticipated problems and adverse events to the IRB is required regardless of the level of monitoring.
Minimal Risk Studies - The PI (or approved co-investigator) will monitor the study with prompt reporting of adverse events and other study related information to the IRB, NIMH, and other agencies as appropriate. Non-serious adverse events and unrelated serious adverse events will be reported in the annual progress report to the NIMH. Serious adverse events that could be related to the study should be reported to the NIMH Program Officer within 7 days of becoming aware of the event. All study deaths must be reported to the NIMH Program Officer immediately. Team meetings by 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 of the study will be reviewed and approved by the NIMH Program Officer and the OCR. This plan will be revised and updated if the benefit-risk analysis changes.

Greater than Minimal Risk Studies - The PI (or approved co-investigator) monitors the study on a day-to-day basis with prompt reporting of adverse events and other study related information to the IRB, NIMH, and other agencies as appropriate. Non-serious adverse events and unrelated serious adverse events will be reported in the annual progress report to the NIMH. Serious adverse events that could be related to the study should be reported to the NIMH Program Officer within 7 days of becoming aware of the event. Team meetings by the PI and his/her staff will be conducted on a routine basis to discuss protocol issues and review adverse events. A Data and Safety Monitoring Plan (DSMP) that addresses the potential risks of the study will be reviewed and approved by the NIMH Program Officer and the OCR. This plan will be revised and updated if the benefit-risk analysis changes. In addition, for clinical trials falling into this risk category, the clinical protocols will be reviewed by the NIMH Program Officer for completeness, including descriptions of participant eligibility criteria, dose escalation plans, criteria defining maximum tolerated dose, and criteria for stopping the trial or the involvement of a subject. For all 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 Data and Safety Monitoring Board 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. Independent Safety Monitor and independent Data and Safety Monitoring Board membership must be approved by NIMH Program and OCR.

Significantly Greater than Minimal Risk Studies - The PI (or approved co-investigator) monitors the study on a day-to-day basis and includes all monitoring activities described above in greater than minimal risk studies. Non-serious adverse events and unrelated serious adverse events will be reported in the annual progress report to the NIMH. Serious adverse events that could be related to the study should be reported to the NIMH Program Officer within 7 days of becoming aware of the event. All study deaths must be reported to the NIMH Program Officer immediately. Significantly greater than minimal risk protocols will also utilize the NIMH-constituted Data and Safety Monitoring Board to monitor the safety and efficacy of the study.