NIMH Policy Governing the Monitoring of Clinical Trials
Replaces Data and Safety Monitoring in Clinical Trials (September 2007)
(Version date: April 16, 2015)
In June 1998, the National Institutes of Health (NIH) issued a policy on data and safety monitoring requiring oversight and monitoring of all NIH funded clinical trials. This monitoring is to be commensurate with the risks, nature, size, and complexity of the trial. For purposes of this policy, NIH defines a clinical trial as a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes . These interventions include drugs, treatments, devices, or new ways of using known drugs, treatments, or devices. Clinical trials are also used to determine whether new biomedical or behavioral interventions are safe, efficacious and effective, and to evaluate the effects or impact of particular biomedical or behavioral interventions. In June 2000, the NIH issued further guidance on data and safety monitoring for phase I and phase II trials .
This National Institute of Mental Health (NIMH) policy outlines the responsibility of the NIMH staff to assure that the appropriate monitoring systems are in place for data and safety monitoring. This policy also assures that the NIMH is notified by NIMH-funded researchers in a timely manner of all directives emanating from monitoring activities. This guidance does not take the place of Institutional Review Board (IRB) guidance, Food and Drug Administration (FDA) requirements, or specific NIH guidelines (e.g., NIH Guidelines for Research Involving Recombinant DNA Molecules), nor should it be used to delay urgent decisions necessary for participant safety.
Consistent with NIH grant policies, after review and approval of the Data and Safety Monitoring Plan (DSMP) by the NIMH Program Officials (PO), investigators shall not modify the DSMP without additional prior NIMH review and approval. Prior approval should be obtained from the NIMH PO and the monitoring entities of record (e.g., IRB, Independent Safety Monitor, and/or Data and Safety Monitoring Board). The NIMH will indicate in the Notice of Award that the recipient may not recruit participants until the NIMH Program staff, the recipient’s IRB, and, whenever applicable, an independent safety monitor (ISM) or data and safety monitoring board (DSMB) have approved the monitoring plan. The NIMH Program staff will consult with the NIMH Office of Clinical Research regarding evaluation of the DSMP as needed.
Data and Safety Monitoring Plans (DSMP)
Applicants seeking NIMH support to conduct clinical trials must include a proposed DSMP as part of the research application. For grant applications, the DSMP will be peer-reviewed and concerns raised by reviewers will be included in the Summary Statement. For grant applications and contracts, the NIMH Program staff will also review applications/proposals and note any concerns related to the need for enhanced monitoring and will communicate such information directly to the applicant. A plan for responding to the concerns will be developed by the applicant, in conjunction with the PO. When modifications to the DSMP are made before the trial begins, a final monitoring plan must also be reviewed by the NIMH and the local IRB prior to initiating trials. The grantee/contractor must promptly request approval from the NIMH PO prior to making any changes in the DSMP during the course of the grant award.
The monitoring activities outlined in the DSMP are to be developed with careful consideration of the relative risks to participants and the nature of the trial. Below is a listing of what, at minimum, should be included in the DSMP. Some of these elements may be discussed elsewhere in the application. If so, the application/proposal sections containing those elements should be referenced within the DSMP and do not need to be repeated.
Critical DSMP Elements
- Summary of the protocol:
- Description of involvement of human study participants (e.g., interventions; scans; biospecimen collections; interviews; screening visits; data from collateral informants including significant others, providers, other observers, etc.)
- List of proposed participating sites or data coordinating centers
- Primary and secondary outcome measures
- Sample size
- Inclusion/exclusion criteria and how the criteria will be evaluated;
- Risks associated with study participation;
- Plans to minimize potential risks due to study participation;
- Description of quality assurance procedures in place to ensure the validity and integrity of the data, such as:
- Sources of material (e.g., questionnaires, medical records, or biospecimens)
- Data confidentiality
- Data security
- Informed consent procedures for all participants or informants, with attention to literacy level of participants;
- Description of entity responsible for monitoring the trial (e.g., IRB, ISM, DSMB) and the frequency of the monitoring activities;
- Description of the process and timeframe for collecting and reporting adverse events and serious adverse events to include: reports made to IRBs, NIMH, FDA and ISM/DSMBs (if applicable). See the NIMH Reportable Events Policy for requirements for reporting event and monitoring entity decisions to the NIMH;
- Plan for management of incidental findings (e.g., aberrant findings on imaging scans or other assessments conducted as part of the research protocol);
- Trial stopping rules (or plans for developing trial stopping rules if appropriate);
- The process for disclosure of any potential conflict of interest (COI) to maintain the integrity of the study; and,
- For multi-site studies, description of the procedures for ensuring compliance with the monitoring plan and requirements for reporting across study sites.
Levels of Monitoring
The NIMH has published guidance on risk-based monitoring to assist with the development of DSMPs. The levels of monitoring are described below.
Monitoring by the Principal Investigator and Institutional Review Board (IRB)
When a trial is of minimal risk to participants and involves only a single site or open-label medication, the NIMH may determine that the study can be adequately monitored by the study Principal Investigator (PI) and the IRB of record. In the event of such a determination, the NIMH expects that the PI will be actively involved in reviewing the progress of each participant on protocol and will report, to the IRB, adverse events and unexpected problems that may influence the IRB’s decision to allow the trial to continue (in accordance with the IRB’s policies). In addition, the NIMH expects the PI to notify the assigned NIMH PO of any reportable events according to the NIMH Reportable Events Policy. Monitoring activities and changes to the study emanating from the monitoring activities must be described in the annual progress report to the NIMH and will be reviewed by the NIMH PO (note: some changes may require prior approval by the NIMH). In the event that the NIMH determines that such a minimal risk trial cannot be monitored adequately by the PI and IRB of record, the NIMH will recommend monitoring by an ISM, as described below.
Monitoring by an Independent Safety Monitor (ISM)
An ISM is an independent physician or other appropriate expert with relevant expertise who advises the grantee/contractor and the NIMH (as appropriate) of any safety concerns. An ISM is recommended for blinded study designs. The responsibility of an ISM is different from that of an internal study medical officer/monitor. The primary responsibility of the ISM is to provide independent monitoring of a clinical trial in a timely fashion. This may be accomplished by review of individual serious adverse event reports immediately after they occur and/or review of periodic cumulative safety monitoring and study progress reports (including participant confidentiality, participant eligibility, recruitment, retention, data quality and management). Based on review of these safety data, the ISM makes recommendations regarding the safe continuation of the study. The ISM must be independent from any professional or financial conflict of interest with the research project and investigators. The ISM may be affiliated with the investigator's institution or other participating sites, but cannot be a scientific collaborator, co-author, supervisor, or subordinate of the investigators. The ISM can be compensated for his/her review time through the NIMH-funded award. The ISM can be blinded or unblinded to the intervention assignment, but must have the option to be unblinded if needed. The monitoring responsibilities of the ISM enhance, but do not replace, the responsibilities of the PI and the IRB (the PI still maintains responsibility for real-time clinical management and for addressing emergent issues). In addition, the NIMH expects the PI to notify the assigned NIMH PO of any reportable events according to the NIMH Reportable Events Policy. Verification of monitoring activities (i.e., ISM approval letter(s) for the reporting period) and changes to the study emanating from the monitoring activities must be included in the annual progress report to the NIMH (note: some changes may require prior approval by the NIMH).
Monitoring by a Data and Safety Monitoring Board (DSMB)
A Data and Safety Monitoring Board (DSMB) is an independent group of experts charged with reviewing study data for data integrity; participant safety; study conduct and progress; and providing directives regarding study continuations, modifications, and terminations. The NIMH allows both external independent DSMBs and NIMH-sponsored independent DSMBs, and the policy on constitution of external independent DSMBs is available. All NIH-sponsored multi-site clinical trials and some single-site clinical trials require DSMB oversight.
DSMBs members are expected to be independent from any professional or financial COI with the research project and investigators. Independence ensures that competing interests do not unduly influence the DSMB and supports objectivity that enhances the safety of participants and the integrity of the trial data. Potential DSMB members will provide the NIMH with qualifications and a COI statement indicating that they have no direct involvement with the study or COI with the investigators or institutions conducting the study. The NIMH expects that reporting requirements and timeframes for serious adverse events (SAE) be outlined in the DSMB’s policy/charter. The SAE report to the NIMH should indicate that the DSMB has been notified in accordance with the approved monitoring plan. The DSMB can be blinded or unblinded to the intervention assignment, but must have the option to be unblinded if needed. The monitoring responsibilities of the DSMB enhance, but do not replace, the responsibilities of the PI and the IRB. In addition, the NIMH expects the PI to notify the assigned NIMH PO of any reportable events according to the NIMH Reportable Events Policy. Verification of monitoring activities (i.e., DSMB approval letter(s) for the reporting period) and changes to the study emanating from the monitoring activities must be included in the annual progress report to the NIMH (note: some changes may require prior approval by the NIMH).