NIMH Policy on Data and Safety Monitoring in Extramural Investigator-Initiated Clinical Trials

Revised September 2007

In June 1998, the National Institutes of Health (NIH) issued a policy on data and safety monitoring that requires oversight and monitoring of all intervention studies to ensure the safety of participants and the validity and integrity of the data. That policy notes that monitoring should be commensurate with risks, and with the size and complexity of the trials. This NIMH policy provides further guidance for monitoring of clinical trials, including studies of already marketed products. It does not take the place of Institutional Review Board (IRB) guidelines, Food and Drug Administration (FDA) requirements, or special NIH guidelines (e.g., NIH Guidelines for Research Involving Recombinant DNA Molecules).

In studies of small numbers of subjects, untoward effects may readily become apparent through close monitoring of individual patients, while in larger studies, risk may best be assessed through statistical comparisons of treatment groups. The NIH requires the use of Data and Safety Monitoring Boards (DSMBs) for phase III clinical trials. For other clinical trials, a DSMB may be appropriate if the studies have multiple clinical sites, are blinded (masked), and/or employ particularly high-risk interventions or vulnerable populations.

For small-scale, single-site, NIMH–supported clinical trials, independent DSMBs may not be necessary, especially when the risk of the intervention(s) is considered relatively low. In most such studies, the Principal Investigator (PI) would be expected to perform the monitoring function as part of the general oversight and scientific leadership of the study. The PI must comply with requirements (see summary below) for prompt reporting of study-related toxicity and of any unanticipated problems involving risks to subjects or others. In some instances, the investigators, IRB, peer reviewers or NIMH staff may determine that an independent individual, committee, or Board is also needed for monitoring.

NIMH-sponsored studies (Cooperative Agreements and extramural contracts) are generally reviewed by an independent NIMH-run DSMB. These Boards are managed by the DSMB Scientific Administrator in the NIMH Office of the Associate Director for Clinical Research. NIMH Intramural Research DSM plans are reviewed by IRBs operating at the Clinical Center and managed by the NIH Office of Human Subjects Research (OHSR).

Research sites typically report their adverse events (AEs) to the local IRB, which will evaluate them and determine whether any additional information or protocol changes are needed. For large multi-site trials comparing intervention/control arms, however, this may be problematic. Local IRBs may not be in the best position to detect problems associated with particular treatment arms across the various study sites. The local IRB sees its own site’s adverse events, but probably does not see those from all sites. And IRBs which do receive AE reports from multiple sites may be inundated with uninterpretable reports. Also, some IRBs may not have sufficient depth of expertise in clinical trials methodology, medical monitoring, statistical analyses, etc. An independent DSMB with relevant expertise can review accumulating data by coded treatment group and across sites, and may detect early signals relevant to safety/toxicity, feasibility, and efficacy in large multi-site clinical trials.

All institutions carrying out an extramural investigator-initiated NIMH-funded intervention study must establish a data and safety monitoring (DSM) plan commensurate with the risks, complexity, and nature of the trial. Unanticipated problems involving risks to subjects or others must be promptly reported to the local IRB (per 45 CFR 46.103b5). The NIMH program officer should also receive timely notification of any study modifications or suspension imposed by the local IRB (i.e., in response to adverse events).

If considered related to such a trial, unanticipated problems involving risks to subjects or others are to be reported to appropriate institutional officials, who will promptly inform the Office for Human Research Protections (OHRP) and the NIMH. Federal Regulations for IND studies require that unexpected serious adverse events (SAEs) associated with the drug (per FDA definitions) be reported to the IRB, the sponsor/manufacturer, and the FDA within 15 days (7 days if life-threatening). For non-IND studies of marketed pharmaceutical products, unexpected SAEs associated with the drug should be reported to the FDA Medwatch Program.

Applications for NIMH Extramural funding of intervention studies must submit a proposed data and safety monitoring plan as part of the research application. This plan will be peer reviewed and any concerns will be included as an administrative note in the summary statement. When modifications to the DSM plan are made before the trial begins (in response to the peer review, IRB review, etc) a final monitoring plan must also be submitted to NIMH and the local IRB. At a minimum, all DSM plans are to include a description of how serious and unexpected adverse events, or unanticipated problems involving risks to subjects or others, will be reported to the local IRB (and to the FDA and /or OHRP as appropriate; see above). Investigators must ensure that the NIMH Program Officer is informed of any actions taken by the IRB as a result of such events.

In multi-site trials, one site may take on reporting responsibilities. Local investigators are to report SAEs, or unanticipated problems involving risks to subjects or others, to their IRB and to any Study Coordinating Center. If such problems are considered related to the trial, then they must also be reported to IRBs at other participating sites, and to the institution/OHRP.

As noted above, NIH requires the establishment of an independent DSMB for multi-site phase III clinical trials. A DSMB should be composed of experts in scientific disciplines needed to interpret the data and ensure participant safety. If the Board notes serious and unexpected adverse events, or unanticipated problems involving risks to subjects or others, which are related to the study, the PIs and IRBs at all participating sites should be notified in a timely fashion. This can be done via a letter from the DSMB Chair/Administrator to the PI (or Coordinating Center), for distribution to the institutional official, sponsor, and the local IRBs. Some DSMBs notify the local IRBs each time the Board reviews study data via a letter that also notes whether serious adverse events (SAEs) were discussed, whether they appeared to be related to the trial, and whether the trial was approved to continue. NIH guidance for reporting adverse events for clinical trials with a DSMB was published in 1999.