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To ensure the safety of research participants, federal regulations require provisions to monitor data collected in the course of a research study, where appropriate. Data and safety monitoring aims both to protect participants and ensure the integrity and validity of research data. All studies involving human subjects require some level of data and safety monitoring. This includes physiologic, toxicity, and dose-finding studies (phase I); efficacy studies (phase II); and efficacy, effectiveness, and comparative trials (phase III). The specific monitoring strategy will depend on the risk, size, and scope of the study, and may involve individuals or groups.

The method and level of monitoring should be commensurate with the degree of risk to subjects and the size and complexity of the study. Generally, minimal risk studies may only require a Data and Safety Monitoring Plan (DSMP) which outlines limited monitoring by the principal investigator (PI) at regular intervals. Higher-risk studies require more frequent monitoring, including outside monitoring. Outside monitors can include an independent safety monitor (ISM), a sponsor-appointed monitoring committee or board, or an outside independent group of experts (often referred to as a Data Safety Monitoring Board (DSMB; also known as a Data Monitoring Committee (DMC)), which conducts interim monitoring, analysis, and oversight. Each NIH IC (Institute and Center) has additional resources / requirements regarding the ISM and the DSMB. Please familiarize with these information.

Data and Safety Monitoring Plans (DSMPs)

When conducting a research study, data safety monitoring is integral to ensuring the safety of all research participants. A DSMP is a written plan for monitoring study data and participant safety. The DSMP ordinarily appears in the study protocol or other document submitted to the IRB and assures that the research study has a system for appropriate oversight and monitoring.

DSMPs are required for all clinical studies that pose minimal or greater than minimal risk. A DSMP should delineate who is responsible for reviewing and reporting adverse events, to whom events are reported, and on what schedule this monitoring and reporting will occur. When an NIH agency requests a copy of the final DSMP for agency approval prior to an award, these plans require approval from your institution.

DSMP Elements

Generally, a written description of a DSMP (either included as part of the protocol or as a separate document) should contain the following elements:

1. The entity (person or committee) responsible for monitoring the overall investigation (as distinct from individual site monitoring for data completeness and accuracy); options include:
   • PI-only; may be sufficient for minimal/low-risk investigations;
   • Study team; appropriate for most observational trials and some multi-center trials;
   • External monitor; an individual not directly involved in the study; may be sufficient for some moderate-risk investigations; and/or
   • Internal Data Monitoring Committee; comprised of two of more individuals from the home institution (but independent of the study team) who have familiarity with the condition under study; may be appropriate for moderate to high-risk single-center investigations.
2. Description of the aspects of the study to be reviewed (e.g. enrollment, adverse events, data completeness, outcome data, protocol non-compliance, new and relevant information, etc.).
3. Frequency of data review and frequency of written reports (if different from the review periods).
4. Plan for adverse event identification and reporting, including:

• Grading scales,
• Attribution scale,
• Methods used to capture adverse events (e.g. subject interview, lab tests), and
• To whom adverse events will be reported, and time frame for reporting.

Note: At a minimum, review of adverse events should occur annually, and reports should go to the IRB, with unexpected and serious adverse events reported and reviewed immediately, as they occur. Office for Human Research Protections (OHRP) regulations require adverse events and unanticipated problems be promptly reported to the IRB of record; guidance specifies reporting these events within five business days. Be aware that some studies may have more stringent monitoring and reporting mechanisms and requirements

1. Data and safety monitoring criteria for decision-making regarding continuation, modification, or termination of the individual participant or clinical study, including interim statistical analysis/early termination rules (if applicable).
2. Plan for monitoring of data quality and accuracy.

A research study that requires an ISM/DSMB should include the elements listed above in the DSMP, along with the appropriate elements in the following section. Though every study will have a DSMP, only a subset of studies will have an ISM/DSMB as one of several components of their safety monitoring plans. The DSMP should specifically indicate whether a formal DSMB will be convened.

Independent Safety Monitor (ISM)

An Independent Safety Monitor (ISM) is a physician with relevant expertise whose primary responsibility is to provide independent safety monitoring in a timely fashion. This is accomplished by review of adverse events, immediately after they occur or are reported, with follow-up through resolution. The ISM evaluates individual and cumulative participant data when making recommendations regarding the safe continuation of the study.

An ISM could be the sole monitor for the study or may perform this role as a member of a Data and Safety Monitoring Board (DSMB). An ISM is appropriate as the sole independent safety monitor for small, early phase studies considered to be low risk, such as some pharmacokinetics or immunogenicity studies, or other studies of short duration. DSMBs should consider the need to designate one or more members as ISM(s). In the case of DSMBs, the ISM focus may be directed at serious adverse events (SAEs) rather than all adverse events (AEs).

Selection and Invitation to Participate

The ISM should be selected based on relevant study-related or therapeutic expertise. Participation is for the duration of the study. The ISM should be able to readily access participant records in real time. He/she is generally a member of the participating institution's staff. The ISM should not be under the direct supervision of the investigator and should preferably be from a different organizational or departmental group.

Conflict of Interest

No ISM should have direct involvement in the conduct of the study. Furthermore, no ISM should have financial, proprietary, professional, or other interests that may affect impartial, independent decision-making. Letters of invitation to prospective ISMs should include the following: "Acceptance of this invitation to serve as the xxx ISM confirms that I do not have any financial or other interest with any of the collaborating or competing pharmaceutical firms or other organizations involved in the study that constitute a potential conflict of interest." In addition, all ISMs will sign a Conflict of Interest certification to that effect at the time they are asked to participate (see ISM COI).

Study Materials for ISM Review

The primary focus of the ISM is to independently review all adverse events and thoroughly investigate those considered serious and unexpected. As the sole monitor, the ISM accomplishes this by evaluating all adverse events against the known safety profile of the study product. Clinical and laboratory data, clinical records, and other study-related records should be made available for ISM review. If necessary, special reports are prepared by the investigator or study statistician.

It is the responsibility of the PI to ensure that the ISM is apprised of all new safety information relevant to the study product and the study. This includes providing the ISM with a copy of the Investigator's Brochure (IB) in advance as well as promptly providing all IB revisions and all safety reports issued by the Investigational New Drug application (IND) sponsor (if applicable). Summary safety and enrollment data should be forwarded periodically to the ISM. The ISM should receive all protocol revisions and may receive other documents relating to the study.

Reports from the ISM

The following reports are submitted by the ISM when acting as the sole independent monitor (otherwise the ISM operates under the guidelines of the DSMB).

A. Review Report: According to pre-specified criteria agreed upon by the NIH Institutes and Centers, the ISM should communicate in writing his/her findings, any concerns and recommendations to NIH IC representatives and, subsequently, the study investigators.

Data and Safety Monitoring Boards (DSMBs)

A DSMB is made up of members from a variety of disciplines who are knowledgeable about, and responsible for, the conduct of research. Membership must include representatives with backgrounds in biostatistics, experimental design, bioethics, and the medical field(s) of concern.

DSMBs are responsible for reviewing data and endpoints on a timeline set forth by the DSMP in the approved protocol. DSMBs are typically required for the following:

1. Studies that pose greater than minimal risk
2. Blinded studies
3. Studies involving new therapies or science
4. Studies involving highly toxic therapies or dangerous procedures
5. Studies involving high expected rates of morbidity or mortality in the study population
6. Studies involving a high chance of early termination
7. Multi-site studies—It is more difficult for an investigator to recognize a pattern of increased or unusual problems when he or she sees only a small fraction of study participants

DSMB Charter

A DSMB charter is a set of written policies that describes the roles, rules, and functioning of the DSMB. Generally, a charter will include:

The purpose of the DSMB;

1. Responsibilities of the members;
2. The operation and format of the DSMB meetings;
3. Monitoring guidelines;
4. Reporting processes (to and from the DSMB);
5. Research data to be monitored, and how data will be provided; and
6. The responsibilities of DSMB administrators.

The charter is intended to be a living document that members may review at any time to determine whether changes in procedure are necessary.

DSMB Charter Templates from the University of Virginia, the NIA, and the CTSA collaborative DSMB workgroup (Appendix C).

The following table presents a checklist for issues about communication of serious adverse events (SAEs) to the DSMB. This table will be equally useful for studies with an ISM.

Issues for Discussion at Orientation Meeting on Serious Adverse Event Data Flow (Adapted from Herson, Jay. Data and Safety Monitoring Committees in Clinical Trials. Chapman and Hall/CRC. 2017. Table 3.2)

1. What information will be in the report?
2. Who at the sponsor will be responsible for communicating SAEs to the DMC?
3. Which SAEs will be reported—all, only those possibly related, and unexpected?
4. Will SAEs occurring on other trials not within the jurisdiction of this DMC be reported to the DMC? By whom? With what frequency?
5. Will the DMC review all deaths, only those related, and only those occurring early in treatment? How will this review be handled?
6. SAEs occurring at any time or only those occurring within 90 days of administration of study drug?
7. Will notification be as the requested SAEs occur or cumulative by week or month?
8. Will the SAE notifications first be sent to the DMC Chair and the Chair will decide what further action is needed or will all DMC members receive the SAE reports at the same time?
9. Will communication of SAEs be via e-mail? If so, this e-mail should be password protected.
10. How often will these SAE reports be updated as new information arrives?

Operations of the DSMB

1. Responsibilities
   • Pre-enrollment meeting: The DSMB may meet prior to the enrollment of the first subject to review the research protocol, informed consent documents, and DSMP. This review allows the DSMB to:
     • Determine the study's risks and benefits, protections in place, and safety of research subjects;
     • Offer suggestions for improving the study design;
     • Reach agreement on the data that will be required for review;
     • Determine the schedule of future meetings
     • Appoint the chair and voting members
     • Decide who receives minutes; and
     • Sign conflict of interest statements.
   • The above issues must be addressed, regardless of whether the DSMB formally convenes for a pre-enrollment meeting.
2. The Pre-enrollment meeting may result in modification of the safety plan provided in the IRB application. If the DSMP is revised, the new plan should be submitted to the institution's IRB and, any applicable advisory committees.
   • Interim data review: The DSMB reviews interim data to detect evidence of efficacy or adverse effects and determines if the trial should continue as originally designed, or whether it should be changed or stopped.
   • Progress evaluation: The DSMB evaluates the progress of the trial, including periodic assessments of data quality/completeness, achievement of recruitment goals, protocol adherence, accrual and retention of participants, and other factors that may affect the study outcome.
   • Protection of confidentiality: The DSMB protects the confidentiality of study participants, trial data, and the results of the monitoring.
3. Membership
   • Appointment: The investigator may independently appoint the DSMB; institution leadership may appoint DSMB members at their institution.
   • Composition: The Board should include three or five members in total (always an odd number). If an efficacy assessment is part of the monitoring plan, a statistical monitoring plan is necessary to ensure the validity of the study and so the board should include a biostatistician. Investigators are encouraged to consider appointment of individuals from different units or divisions from within their institution, and beyond. Board membership must be determined and described prior to submitting a project for scientific and human subjects review.
   • Qualifications and responsibilities: Qualifications for membership are:
     • Expertise in the field,
     • Experience in conduct of human subjects research and statistical knowledge,
     • Independence from the direct management of the research study, and
     • Absence of conflict of interest or other conflicting commitment (i.e., must not be a co-investigator, should not be a direct report of any PI or co-investigator)
4. A chairperson will be appointed, and will be responsible for overseeing the meetings, developing the agenda, and summarizing the meeting. The chairperson is the contact person for the DSMB

Timing and Frequency of Meetings

DSMB meetings will take place at least annually. The board may choose to meet periodically (e.g., quarterly or semiannually) if the risk to the subject is high, the population is vulnerable, there is a large volume of data to review, and/or after a pre-determined number of subjects have accrued. The chair may also call ad hoc meetings depending on safety or efficacy concerns. Meetings may be conducted by teleconference at the request of the board members

Meeting Agenda

1. The board will review required data (determined at the pre-enrollment meeting) provided by the investigator.
2. As per the DSMP, The board will:
   • Determine if the study has adhered to the treatment plan
   • Review interim analysis, if applicable, and determine specific data to be analyzed
   • Evaluate end point/stop point rules
   • Review protocol violations and deviations to assess adequacy of the protocol
   • Ensure appropriate documentation of informed consent
   • Review current enrollment information to:
     • Determine whether enrollment has followed eligibility criteria
     • Ensure accrual is on target
     • Assess visit compliance
     • Review screening failure information
   • Review IND/IDE information
   • Discuss investigator or key personnel changes
   • Review completeness and quality of data collection forms
   • Evaluate the aggregate analysis of adverse events/serious adverse events
   • Review vital signs, clinical tests, etc.
   • Review confidentiality

Meeting Outcome

The major outcomes following data review include:

1. Continuation of the trial, unchanged
2. Modification of the protocol and/or consent form (for example, it may be unethical to continue giving a placebo after a new treatment has been proven to be effective, or to continue a new treatment when there is no chance the trials will be positive)
3. Termination of the trial

Minutes and Reporting

Minutes from each meeting will be maintained.

The investigator should not be present for at least part of the meeting. Following the meeting, a report should be provided to the investigator, the IRB, the sponsor, and if necessary, study participants. The report should indicate whether the study should continue as originally designed, be modified to protect patient safety, or be terminated.

References

The information are adapted from:

1. Harvard Clinical & Translational Science Center Data And Safety Monitoring Guidance
   

2. NIDCR Independent Safety Monitor Guidelines

3. Herson, Jay. Data and Safety Monitoring Committees in Clinical Trials. Chapman and Hall/CRC. 2017

4. DSMB Training Manual v1.0 by the CTSA collaborative DSMB workgroup.

Additional Resources

1. Data and Safety Monitoring Board Training Manual for investigator-Initiated Studies by the CTSA Collaborative DSMB Workgroup

2. An explanation of what are Data and Safety Monitoring Plans and Data Safety Monitoring Boards by the IRB-HSR

3. NIH Guidelines for Establishing and Operating a Data and Safety Monitoring Board

4. NIA Guidance on Clinical Trials

5. NIAAA Guidelines for establishing and operating a Data and Safety Monitoring Board (DSMB)

6. NIDCD Guidelines for Data and Safety Monitoring of Clinical Trials

7. NIDCR Data and Safety Monitoring Board (DSMB) Guidelines

8. NIDDK policy on Data & Safety Monitoring Plans

last updated: 2022