NHLBI Policy for Data and Safety Monitoring of Extramural Clinical Studies

National Heart, Lung, and Blood Institute
National Institutes of Health

October 2011: updated December 2014

PURPOSE

The purpose of this document is to outline the National Heart, Lung, and Blood Institute (NHLBI) policy for data and safety monitoring of clinical studies for all human subjects research funded in whole or in part by the NHLBI. The 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 NHLBI responsible for oversight of data and safety monitoring to ensure that an appropriate monitoring system is in place for all NHLBI-supported trials and that the Institute is informed in a timely manner of all recommendations emanating from monitoring activities. It does not usurp the role of Institutional Review Boards (IRBs) or other regulatory and monitoring bodies; the policy simply makes clear that the role of the NHLBI is to ensure that appropriate approvals have been obtained. Release of funds for human subjects research activities is contingent upon compliance with this policy.

DEFINITIONS

Refer to NHLBI Clinical Research Guide Glossary for additional terms not identified.

POLICY DETAILS

NIH Policy

For all interventional trials, the NIH requires documentation of an IRB-approved data and safety monitoring plan (DSM Plan).  NIH further requires, as part of the DSMP, the appointment of a Data and Safety Monitoring Board (DSMB) for all clinical trials that involve:

  • investigation of a research question having direct implications for clinical care and/or public health (including all Phase III trials), and/or
  • a high-risk intervention, and/or
  • a highly vulnerable patient population.

NHLBI Policy

NHLBI expands the NIH policy for an IRB-approved DSM Plan to include all human subjects research that involves greater than minimal risk to participants (as determined by the IRB). 

  • DSM Plans must be approved by the IRB and NHLBI prior to study initiation.

NHLBI also requires that all multi-center trials have either a local or an NHLBI-appointed DSMB:  

  • NHLBI will appoint the DSMB for multi-center trials conducted in research networks, and for trials performed under a contract or a cooperative agreement.  
  • NHLBI can also appoint a DSMB for trials funded under other mechanisms, depending on assessment of the risks involved. 
  • For all other multi-center trials, a DSMB will be appointed by the awardee institution.
  • A local DSMB may be converted to an NHLBI-appointed DSMB if circumstances change as a trial progresses. 

For epidemiological studies and registries involving multiple sites and/or conducted under a contract or cooperative agreement, the NHLBI may appoint an Observational Study Monitoring Board (OSMB), or may ask the local institution to appoint one.

For operational details refer to the FAQs.

IMPLEMENTATION

Data and Safety Monitoring Plans:

  • Data and safety monitoring plans, when required, must:
    • Identify the entity that will monitor the study. Monitoring may be conducted in various ways or by various individuals or groups -- depending upon the size and scope of the research effort, it may be performed by the Principal Investigator (PI), an independent monitoring group, a DSMB, or an OSMB. For studies with low risk, monitoring by the PI and the IRB may suffice; for higher risk studies, a DSMB may be required.
    • Describe 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), NHLBI, and FDA (if applicable).
    • For multi-site studies, describe the procedures for ensuring compliance with the monitoring plan and requirements for reporting across study sites.
      (See: Data and Safety Monitoring Plan Checklist)
  • Certification of IRB approval(s) of a protocol with its data and safety monitoring plan must be sent (preferably electronically) to the NHLBI Grants Management Officer (GMO) before a proposed human subjects research project may begin at a site. For multi-site studies, the Data Coordinating Center (DCC) and study sites initiating a protocol 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 NHLBI upon request.
  • PIs must submit annual progress reports that:
  • Confirm adherence to the data and safety monitoring plan.
  • Include a summary of any data and safety monitoring issues that occurred since the previous reporting period.
  • Describe any changes in the research protocol or the data and safety monitoring plan that may or does affect risk.
  • Provide all new and continuing IRB approvals.

If an IRB-approved data and safety monitoring plan is not provided for a study that requires a data and safety monitoring plan, the NHLBI may request certification by an appropriate official of the awardee institution that its IRB has concluded that the proposed research is neither a clinical trial nor a study that involves greater than minimal risk to participants.

Monitoring Board Operations for DSMBs and OSMBs

Monitoring Board Principles:

  • NHLBI monitoring boards:
    • Are convened to protect the interests of research subjects and ensure that they are not exposed to undue risk.
    • Operate without undue influence from any interested party, including study investigators or NHLBI staff.
    • Are encouraged to review interim analysis of study data in an unmasked fashion. If a board decides 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.
  • NHLBI staff who function as Project Scientists for a study should not be privy to post-randomization data broken down by treatment group that may be discussed during closed board meetings.
  • 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 NHLBI staff, including NHLBI statistician(s) who are overseeing the analysis. Details may vary by study.

Board Membership:

Monitoring boards are either appointed by the NHLBI and act as an independent advisory group to the NHLBI Director, or are appointed locally for investigator-initiated studies. The NHLBI program office, in consultation with the PI and the respective institution, will determine if a locally-appointed monitoring board is appropriate for a given investigator-initiated study. Generally both types of 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.

Every board must have an executive secretary who is not otherwise involved in the study or with the study team.

  • For NHLBI-appointed boards, the executive secretary is either a NHLBI employee with clinical trial expertise or a contractor.
  • For locally-appointed boards, the executive secretary is usually a member of the monitoring board.

Each monitoring board must have a chair 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.

Defined terms for members of NHLBI-appointed boards.

  • 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.
  • 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:

Alll Monitoring boards must:

  • Have a charter that has been reviewed and approved by the board and accepted by the NHLBI program office. (see ).
  • Approve the study protocol, including the data and safety monitoring plan, informed consent template, reporting templates for data to be presented to the board, and anything else the board may wish to see before a study can begin enrollment.

Monitoring board meeting minutes must summarize the topics discussed and list the all recommendations, and must be signed by the board chair. After each board meeting, throughout the active phase of a study, the lead investigators must arrange for a summary of board recommendations to be sent to each participating IRB.

  • For NHLBI-appointed boards, the NHLBI ES is responsible for preparation and transmission of the formal DSMB minutes to the Director of the applicable Division within 14 calendar days of each meeting or call. The NHLBI program office will prepare a Summary Report of Board Recommendations and submit it to primary study investigators(s) and DCC within 30 calendar days of each meeting, if the DSMB does not identify any safety or other protocol-related concerns.  If the DSMB does identify concerns, the NHLBI staff will distribute, as soon as feasible, preferably within 7 calendar days of the DSMB meeting. Primary study investigators(s) or DCC will forward the Summary Report to each participating research site.
  • For locally-appointed monitoring boards, minutes or meeting summaries and the PIs’ follow-up plans must be submitted to NHLBI program staff and the board within the timeline specified in the board charter. Minutes need not be sent to the NHLBI Division Director unless requested.

Conflicts of Interest (COI) for board members must be reviewed and managed appropriately.

  • For NHLBI appointed boards, COIs are reviewed by the executive secretary and the NHLBI ethics officer.
  • For locally appointed monitoring boards, institutions are expected to have a COI policy and/or plans for management and monitoring of COIs.

Format of Board Meetings:

Board meetings generally have an Open Session, a Closed Session (for DSMBs only), and an Executive Session.

Open Session:

  • For NHLBI-appointed boards, a board may limit the number of non-board members in attendance. The number of coordinating center and NHLBI representatives in attendance should be limited so as not to overwhelm free and open exchange among board members.
  • For locally-appointed monitoring boards, NHLBI program staff may participate (but not vote) in the open session unless the board chair decides that the presence of NHLBI staff may inhibit free and open discussion, or compromise or appear to compromise the board’s independence. The issue should be addressed in the board charter. The NHLBI program official 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.

Closed Session:

  • For NHLBI-appointed boards, staff participation in closed sessions when unmasked outcome data by treatment arm will be discussed, is restricted to unmasked NHLBI and Coordinating Center staff.  For NHLBI, this would usually be the executive secretary and the designated NHLBI study statistician. Additional NHLBI representatives must be approved by the program official in consultation with the executive secretary and the DSMB Chair. However, if other topics are to be discussed in closed session, such as site performance, additional NHLBI staff would participate.
  • For locally-appointed boards NHLBI staff participation is at the discretion of the DSMB Chair.

Executive Session:

  • For NHLBI-appointed boards, the DSMB may hold an executive session in which only the DSMB members are present. The NHLBI ES may attend the executive session at the invitation of the DSMB Chair.  If the ES does not attend the executive session, the DSMB Chair will be responsible for summarizing the DSMB’s discussion and recommendations to the ES.
  • For locally-appointed boards NHLBI staff participation is at the discretion of the DSMB Chair.

REFERENCES

For questions and/or concerns regarding the content of this page, please contact the NHLBI_OCR@mail.nih.gov.

Last Updated: December 2014