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Policy for Data and Safety Monitoring of Human Subject Research Studies

Purpose

This document outlines the National Institute of Environmental Health Sciences (NIEHS) policy for data and safety monitoring of all human subject research studies funded in whole or in part by the NIEHS. The National Institutes of Health (NIH) requires the monitoring activities of all NIH-sponsored or -conducted clinical studies to be commensurate with their risks, nature, size, and complexity. This policy complies with the NIH mandate by making the NIEHS responsible for oversight of data and safety monitoring to ensure that an appropriate monitoring system is in place for all NIEHS-supported human subject research and that the Institute is informed in a timely manner of all recommendations emanating from monitoring activities. Release of funds for human subject research activities is contingent upon compliance with this policy.

Definitions

Data and Safety Monitoring Plan (DSMP) - A written description of the procedures for reviewing accumulated data in an ongoing research protocol to ensure the safety of research participants and the continuing validity and scientific merit of the protocol.

NIH Definition of a Clinical Trial - 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.

Data and Safety Monitoring Board (DSMB) (also known as a Data and Safety Monitoring Committee [DSMC] or Data Monitoring Committee [DMC]) - A formal committee made up of experts, who are not the trial organizers or investigators, which reviews on a regular basis accumulating data from one or more ongoing clinical trials.

Policy Details

Human Studies Requiring a DSMP

NIEHS requires all extramural applications for interventional clinical trials and all protocols that are subject to intramural NIH institutional review board (IRB) approval to include a DSMP. NIEHS is committed to supporting the operations of the approved DSMP. The method and degree of monitoring should be commensurate with the degree of risk involved in participation and the size and complexity of the study. In general, the DSMP will include selection of a data and safety monitoring mechanism. Appropriate mechanisms for data and safety monitoring range from monitoring by the Principal Investigator (PI) or Associate Investigator (AI), to monitoring by an independent DSMB. For example:

  1. Monitoring by the PI or AI or other designated individual may be appropriate for protocols involving no more than minimal risk or a minor increase over minimal risk and that are conducted at a single site.
  2. Monitoring by an individual or team that is independent of the protocol may be appropriate for protocols that pose more than minimal risk to the subjects, for multi-site protocols, for studies where an investigator has a potential conflict of interest, or for some FDA-regulated research.

Human Studies Requiring a DSMB

Federal regulations only require a DSMB for research studies in emergency settings in which the informed consent requirement is excepted [21 CFR 50.24(a)(7)(iv)]. NIEHS operationalizes the NIH DSMB policy and guidance by requiring DSMB oversight for, at a minimum, all randomized clinical trials that involve investigator-masked interventions, complex design, greater than a minor increase over minimal risk, and enrollment of greater than 100 subjects. Additional factors that must be considered for DSMB oversight are long duration, high-risk interventions, vulnerable populations, significant public health impact, or high public interest and concern. The IRB of record, the Program Official (PO) for extramural studies, or the Clinical Director (CD) for intramural studies may also require a DSMB.

Implementation

Operations for DSMPs

If an IRB-approved DSMP is not received for an extramural study that, in the opinion of the PO, requires a DSMP, the NIEHS may request certification by an appropriate official of the awardee institution that the IRB of record has concluded that the proposed research is not an interventional clinical trial and does not require a DSMP.

A DSMP must be included in all intramural NIH IRB applications and will include the procedures for: monitoring study safety; minimizing research- associated risk; protecting the confidentiality of participant data; and identifying, reviewing, and reporting adverse events and unanticipated problems to the IRB(s), NIEHS, and Food and Drug Administration (FDA) (if applicable).

DSMPs will address the following as appropriate:

  1. Monitoring mechanism: The individual(s) who will be responsible for the data and safety monitoring should be identified. When a DSMB is the monitor, the PI will provide the names of the DSMB chair, secretary and members and who is establishing the DSMB.
  2. Frequency of monitoring: Monitoring should be performed on a regular basis at intervals determined before the study begins.
  3. Stop or change rules: Specific criteria to be used for interrupting enrollment or administration of study products or procedures and formal guidelines to be used for stopping one or more study arms should be provided.
  4. Advanced plans for any interim analyses and/or futility analyses.
  5. Information to be monitored: In describing what information will be monitored, consideration will be given to the following, as appropriate:
    1. An evaluation of the progress of the research study, including assessments of data quality and timeliness and participant recruitment, accrual and retention consistent with plans for diversity and generalizability.
    2. A review of adverse event and outcome data to determine whether there is any change to the risk/benefit ratio of the study, if a stop rule has been invoked, a study endpoint has been reached, and whether the study should continue as originally designed, be changed, or be stopped.
    3. An assessment of external factors or relevant information (e.g., developments in the literature, results of related studies, etc.) that may have an impact on the safety of participants or on the ethics of the research study.
  6. Communication: The lines of communication between the PI, the study sites, research teams, the data and safety monitor/committee, the IRB, the FDA, and other individuals at the NIH should be identified.

PIs for studies must submit, at a minimum, annual progress reports to the PO for extramural studies or to the CD for intramural studies that:

  1. Confirm adherence to the DSMP.
  2. Include a summary of any data and safety monitoring issues that occurred since the previous reporting period.
  3. Describe any changes in the research protocol or the DSMP that may or does affect risk.
  4. Provide all new and continuing IRB approvals.

Operations for DSMBs

DSMBs:

  1. Are convened to protect the interests of research subjects and ensure that they are not exposed to undue risk.
  2. Are advisory to the sponsor of the study and operate without undue influence from any interested party, including study investigators or NIEHS staff.
  3. Must be informed by NIEHS of their ability to access unmasked data.
  4. Are encouraged to review interim analyses of study data in an unmasked fashion as needed to assess the risks and benefits in the study. In the charter, the board should define the timing and conditions for assessing unmasked data. If data are to remain masked for a certain period of time, rigorous stopping rules should be outlined at the onset of the study and documented in the board’s charter.

For an extramural protocol, certification of IRB approval(s), and the DSMB plan if needed, must be sent electronically to the appropriate PO and approved before a proposed human subject research project may begin at a site. All other related documents for an extramurally funded study will also be sent to the PO and archived in the main grant file as a permanent repository of study decisions and progress.

For intramural studies, all supporting documents will be sent to the NIH IRB of record after approval by the CD.

For multi-site studies, the study sites initiating a protocol and the Data Coordinating Center (DCC) must submit certification of IRB approval as well as assurance that IRB approvals have been obtained from all study sites, are on file, and are available to the NIEHS upon request.

For extramural studies, the DSMB members will be proposed, after PI consultation, by the awardee institution, who will assure that there are no conflicts of interest. For intramural studies, board members will be proposed, after PI consultation, by the CD. The DSMB will meet after IRB approval of the study but before enrollment of subjects.

Each DSMB must operate according to the provisions of a formal charter (see the NIEHS Monitoring Board Charter Template at Data Safety and Monitoring Board Charter ), agreed to in advance by DSMB members and then approved by the PO for extramural studies and the CD for intramural studies. Charters should address appointment and responsibilities of members, terms of appointment, scheduling and format of meetings, quorum requirements, distribution and disposition of meeting materials, preparation of meeting summaries and written recommendations, management of conflict of interest, voting rights, and other procedural matters.

The charter should provide a clause that would permit procedures to be changed as necessary. Any potential participation of the PO or CD and their designees will be outlined in the DSMB charter. NIEHS staff (PO or CD or their designees) should not be privy to post-randomization data broken down by treatment group that may be discussed during closed board meetings. NIEHS staff (PO or CD or their designees) who are approved to attend DSMB closed board meetings, must remain objective about the outcome(s) of the study and must not influence the recommendations of the DSMB. Access to unmasked data must be limited to board members and a small group of additional individuals who are to be determined at the onset of the study. Typically the additional individuals will include DCC staff directly involved in the analyses and designated NIEHS staff, including NIEHS or other statistician(s), who are overseeing the analysis. Details may vary by study.

Appropriate NIEHS staff will be trained in their roles and responsibilities related to oversight of monitoring when attending board meetings. For extramural studies the Director, Division of Extramural Research and Training, and for intramural studies the CD, will be available to discuss any board member concerns related to NIEHS staff attendance or participation at meetings.

Board Membership

Monitoring boards should function in accordance with criteria described below, and essential elements of the board must be included in the data and safety monitoring plan (see: Establishment and Operation of Clinical Trial Data Monitoring Committees for Clinical Trial Sponsors, http://www.fda.gov/RegulatoryInformation/Guidances/ucm127069.htm).

  1. Each monitoring board must have a Chair, an executive secretary for assuring the accuracy and timely transmission of the final recommendations and meeting minutes and members who are independent of the study and generally have expertise in biostatistics, epidemiology, clinical trials, bioethics, and key subject areas involved in the research. The board members, Chair and executive secretary will be proposed by the awardee institution (for extramural studies) or the CD (for intramural studies). The Chair and executive secretary will be approved by other members of the board. It is often useful to have odd numbers of board members so that a majority vote will be facilitated.
  2. Conflicts of Interest (COI) for board members must be reviewed and managed appropriately. For boards overseeing extramural studies, awardee institutions are expected to have a COI policy and/or plans for management and monitoring of COI. For boards overseeing intramural studies, members must complete the NIEHS COI and confidentiality statement (see Data And Safety Monitoring Board Form ) that is approved by the NIEHS ethics officer.
  3. Defined terms for members of NIEHS-appointed boards.
    1. In general, members will be appointed for a term that will coincide with the duration of the study or the award. For studies that continue beyond a single award period, board members’ service will be evaluated at the time of the new award, and may be renewed, based on expertise, contributions and participation, and study needs.
    2. When specialized expertise is needed for a short period of time, ad hoc members can also be appointed to boards with shorter terms of service.

Management of Reports and Other Study Documentation:

  1. All Monitoring boards must have a charter that has been reviewed and approved by the board and accepted by the NIEHS PO for extramural studies or the appropriate compliance office and CD for intramural studies (see NIEHS Monitoring Board Charter Template, Data Safety and Monitoring Board Charter ).
  2. Monitoring board meeting minutes must summarize the topics discussed and list all recommendations, and must be signed by the board Chair. After each board meeting, throughout the active treatment phase of a study, the PI must arrange for a summary of board recommendations to be sent to each participating IRB. Board minutes must be submitted to the PO for extramural studies, or the appropriate compliance office and CD for intramural studies, and to PIs, who then submit them to all participating IRBs within the timelines specified in the charter.

Format of Board Meetings

Board meetings generally have an Open Session, a Closed Session, and an Executive Session.

  1. Open Session:
    1. The NIEHS PO (for extramural studies) or the CD (for intramural studies) should be informed of upcoming board meetings at least 1-2 weeks in advance, and receive the appropriate meeting materials at the same time as the board members. NIEHS staff who are not DSMB members are only attending as observers, and are not, even in an informal capacity, considered to be a DSMB member.
    2. A board may limit the number of non-board members in attendance. The number of NIEHS representatives in attendance should be limited so as not to overwhelm free and open exchange among board members.
  2. Closed Session:
    1. NIEHS staff attendance is at the discretion of the DSMB Chair. If invited, NIEHS staff attend only as observers and will make comments only if asked questions by the DSMB.
    2. NIEHS staff attendance in closed board sessions when unmasked data will be discussed is restricted to unmasked NIEHS staff. This would usually be the executive secretary and the designated study statistician. Additional NIEHS representatives must be approved by the DSMB Chair.
  3. Executive Session:
    1. NIEHS staff attendance is at the discretion of the DSMB Chair. If invited, NIEHS staff attend only as observers and will make comments only if asked questions by the DSMB.
    2. NIEHS staff are not required to attend the Executive Session, however, the DSMB Chair may ask the executive secretary to remain in the Executive Session at their discretion. The DSMB Chair will record minutes/recommendations during the Executive Session when the executive secretary is not present.