Data & Safety Monitoring Plans
As required by the NIH Further Guidance on a Data and Safety Monitoring for Phase I and Phase II Trials and NIH Policy for Data and Safety Monitoring, the NIDDK has developed guidelines to provide a uniform structure for all NIDDK grant applicants and grantees conducting human subjects research. This webpage provides guidance for NIDDK grant applicants on
- who needs a data and safety monitoring plan (DSMP)
- the content of a DSMP
- which clinical studies require a Data and Safety Monitoring Board (DSMB)
- DSMB responsibilities
- template documents for DSMPs and DSMBs
Who Needs a Data and Safety Monitoring Plan (DSMP)
All NIH grant applications involving human subjects research must include a section on Protection of Human Subjects. NIDDK requires that all grant applications involving human subjects (i.e., not just clinical trials) must include both a section on Protection of Human Subjects and a DSMP.
Prior to the issuance of a Notice of Grant Award, NIDDK staff must review and approve the DSMP. NIDDK may require a more detailed plan than was included in the grant application. Investigators are encouraged to contact their program officer with any questions.
Content of a Data and Safety Monitoring Plan (DSMP)
DSMPs are designed to ensure the safety of participants and assure the validity of data. In addition, such plans should allow for the appropriate termination of clinical studies for which significant benefits or risks have been uncovered or when it appears that the study cannot be conducted successfully. The DSMP should be commensurate with the risk, size, and complexity of the study.
NIDDK requires DSMPs to include a description of:
- Potential risks to participants
- Adverse events expected because of the underlying condition;
- Known side effects of the intervention;
- Risks or complications of the outcomes being assessed;
- Actions to be taken to minimize or mitigate these risks.
- Safety Reporting
- The plan should include a description of the adverse events expected because of the underlying condition, the known side effects of the intervention, and any risks or complications of the outcomes being assessed. Steps to be taken to minimize risk should be described.
- The plan should describe what adverse events will be tracked, how this will be accomplished and how the adverse events will be reported.
- The plan should describe who has the responsibility for reporting, and the roles and responsibilities of each person on the clinical study team who is involved in safety reporting.
- The plan should include the timeline for reporting of serious adverse events (SAEs) and targeted non-serious adverse events (AEs) to the entity doing the monitoring, the IRBs and the FDA, if applicable. More information about investigational new drug (IND) safety reporting is available at 21 CFR 312.32. Any unexpected safety events and SAEs related to the study should be reported to NIDDK. Regardless of whether the study is conducted under an IND, reporting of deaths, SAEs, and unanticipated problems to the IRB and NIDDK is generally expected to adhere to the timelines outlined for reporting to the FDA. Investigators involved in multi-center clinical studies must ensure that a summary of the Data and Safety Monitoring Board (DSMB)’s review of adverse events be distributed to all site IRBs (see NOT 99-107). For investigator-initiated clinical studies, a summary of the meeting or the minutes from meetings with the Safety Monitor or DSMB (see below) should also be sent as an official communication to NIDDK.
- The plan should include the timeline for reporting any IRB actions to NIDDK.
- Safety Monitoring
- The overall framework for safety monitoring and what information will be monitored.
- The frequency of monitoring.
- The plan should discuss who is responsible for monitoring and how that monitoring will occur. The monitoring plan should be commensurate with the risk, size and complexity of the study. Monitoring may range from a single Safety Officer to a DSMB. For studies not requiring a DSMB, a Safety Monitor should be designated. In general, the Safety Monitor should not be an individual involved in patient care as part of the study and it is preferable to have a Safety Monitor who is external to the clinical study. The Safety Monitor and DSMB members must be free of any conflicts of interest so that independence and objectivity are maintained. Potential conflicts of interest for the safety monitor/DSMB members include: 1) financial conflicts; 2) publication or collaboration with study investigators; and 3) the potential monitor is subordinate to the study investigator. If the trial is not masked and is low risk, it may be appropriate for the principal investigator (PI) to be involved with oversight of the study in conjunction with the external Safety Monitor. If there is no external monitor, the plan should include a discussion of how the Institution will avert or manage any conflict of interest (COI) implicit in having the Principal Investigator, or person directly reporting to the PI, as the only monitor of a clinical study. The plan should specify how COI will be ascertained and tracked. For masked studies, the plan should make clear how masking is maintained and under what circumstances unmasking would occur as well as who would be unblinded. Studies conducted in a clinical studies unit may be monitored by its designated team.
- Quality Assurance
- A description of a plan to ensure adherence to the protocol, and the quality and consistency of the intervention(s), including the frequency of monitoring, and a description of protocol adherence and data quality control to date.
- A description of how participant accrual and retention will be monitored, including any tracking by sub-group (e.g., age, gender, race/ethnicity). For multi-site studies, plans should be made for monitoring by site and in aggregate.
- A description of plans to ensure participant confidentiality and privacy. Staff should keep in mind that the increasing use of mobile devices in clinical studies may pose privacy concerns.
- A description of plans to ensure the quality of all data collected, including laboratory measures.
- Plans for handling any deficiencies that are uncovered.
- Statistical Analysis
- The plan should include the power calculation(s) to demonstrate feasibility.
- There should be discussion of any planned interim analyses, including adjustments for spending “alpha” on “multiple looks.”
- Stopping rules for clinical trials should also be specified. Generally, stopping rules reflect one of the following conditions: 1) there is clear evidence of harm; 2) there is no likelihood of demonstrating treatment benefit (futility); 3) there is overwhelming evidence of the benefit of treatment.
- Conflict of Interest
- The plan should discuss how investigator conflicts of interest will be handled.
Clinical Studies that Require a Data and Safety Monitoring Board (DSMB)
The purpose of the DSMB is to ensure participant safety and oversee the conduct of studies that are large, complex or high risk. NIDDK requires a DSMB for the following clinical studies:
- All phase 3 trials - NIH requires a DSMB for all phase 3 clinical trials. Generally, these trials are large, masked, involve multiple sites, and are intended to change medical practice or product labeling. These characteristics warrant a high level of impartial scrutiny.
- Phase 1 or 2 trials that involve masked interventions- The use of a DSMB ensures oversight of participant safety while the clinicians involved in conducting the study remain blinded to outcome and safety data.
- Multi-center clinical studies- Multi-center studies involve multiple institutions following the same protocol. This imposes a level of complexity which will benefit from impartial scrutiny of safety, study conduct and data quality/ integrity, to ensure that all sites are conducting study procedures in a similar, uniform manner.
- Clinical trials of high risk interventions or clinical studies where the outcome assessment is invasive or involves more than minimal risk- Studies of high risk interventions (e.g., gene transfer studies; drug with significant toxicities) should be monitored by a DSMB. Trials that involve testing of new interventions where limited safety data is available are also considered high risk. In addition, studies where the measured outcome is used solely for research purposes and is invasive or could potentially have adverse effects should utilize a DSMB. Please note that the concept of minimal risk is not up to the investigator, but is defined in 45 CFR Subpart A, Sec. 46.102.
- Clinical studies involving vulnerable populations that are more than minimal risk- The term “vulnerable populations” generally encompasses children, pregnant women, prisoners, elderly or terminally ill individuals, or those with diminished mental capacity. Generally, such studies should be monitored by a DSMB. However, in a single center study, if the intervention or outcomes assessment poses only minimal risk, it may be acceptable to have a Safety Monitor, rather than a DSMB. Such exceptions should be discussed with the appropriate NIDDK program staff. NIDDK, however, may require institution of a DSMB for minimal risk studies based on the population or study design.
Data and Safety Monitoring Board (DSMB) Responsibilities
The responsibilities of the DSMB should include:
- Review the protocol, informed consent documents, and data and safety monitoring plans (DSMPs);
- Consider major changes to the research protocol, informed consent documents and DSMPs;
- Evaluate the progress of the study, including periodic assessments of data quality and timeliness, participant recruitment, accrual and retention, participant risk versus benefit, performance of the study sites, and other factors that may affect study outcomes;
- Review serious adverse events and other safety reports and make recommendations regarding protection of the safety of study participants;
- Ensure data integrity and confidentiality;
- Review areas of concern regarding the performance of individual sites and provide comment on actions to be considered regarding sites that perform unsatisfactorily;
- Consider factors external to the study when relevant information becomes available, such as scientific or therapeutic developments that may have an impact on the safety of the participants or the ethics of the study;
- Modify the study protocol or make recommendations regarding possible early termination of the study because of attainment of study objectives, safety concerns, low likelihood of showing a benefit of the intervention (futility), or inadequate performance (such as enrollment and retention problems);
- Review the interim analysis of efficacy, if appropriate, in accordance with stopping rules which are clearly defined in the protocol;
- Provide input on the desirability of proceeding to the full-scale study at the completion of a feasibility phase, if appropriate;
- Assess the potential impact of ancillary studies on the integrity of the parent study; and
- Monitor clinical ancillary studies unless an independent monitoring system is used.
The size of the DSMB will depend on the nature and complexity of the study. Members should have expertise appropriate to the science of the study and clinical trial design. At least one biostatistician should be included. For investigator-initiated studies that are not cooperative agreements, the grantee will generally appoint the members of the DSMB. However, the composition of the DSMB must be approved by NIDDK as part of its review of the data and safety monitoring plan (DSMP). The members of the DSMB must be independent from the study staff and anyone responsible for patient care in the study. DSMB members should not have any scientific, financial or other conflict of interest related to the study. Written documentation attesting to absence of these is required. Waivers may be granted by the NIDDK based on specific considerations.
The DSMB should have a charter that describes its responsibilities and operating rules. A sample DSMB charter is provided in the Templates Documents section.
Each DSMB meeting will have an open session, which includes the principal investigator (PI) and the study statistician. The open session generally focuses on study conduct (e.g., recruitment and retention; data quality) and allows the DSMB to interact with study leadership and raise issues about the conduct of the study. Outcome data should not be presented in the open session.
Following the open session, the DSMB meets in closed session with the unmasked study statistician(s) who will present outcomes data and answer questions. The DSMB should then have time to deliberate without any study staff present.
There should be a summary of each meeting, noting the date/time and means of communication (e.g., in-person, teleconference, etc.), participant list and recommendations. The PI should communicate the deliberations of the DSMB to any other investigators involved with the study, the IRB, NIDDK, and, if appropriate, applicable regulatory agencies. The PI must notify NIDDK of any actions taken by the IRB.
The documents below are meant to provide assistance for NIDDK grant applicants and are simply examples that can be customized and used as needed for each individual study. There is no requirement to use these particular documents, and investigators are free to use their own materials.
- Clinical Study Tracking Template (PDF, 29 KB)
- Sample Data and Safety Monitoring Board (DSMB) Charter (PDF, 71.92 KB)