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Microbiology and Infectious Diseases Clinical Research

Safety Oversight

National Institutes of Health (NIH) policy requires that each Institute and Center have a system for managing/implementing the appropriate oversight of the conduct of clinical trials that ensures the safety of participants and the validity and integrity of the data. The NIAID Division of Microbiology and Infectious Diseases (DMID) extends this requirement to other clinical research where there are safety concerns. Data and safety oversight provides independent and objective review of the overall conduct of the study. Data Safety and Monitoring Boards (DSMBs) review both interim safety and other clinical endpoint data (e.g., surrogate markers). Safety Monitoring Committees (SMCs) review safety data. These oversight committees provide recommendations to DMID and the study investigators as to the appropriateness of continuing the study as designed or described in the protocol. These recommendations address whether the study (or intervention for an individual or study cohort) should continue per protocol, be halted while additional information is gathered, be discontinued, or be modified. The DSMBs and SMCs are advisory to DMID, and their recommendations, while given careful consideration, are not binding.

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)]. NIAID operationalizes the NIH DSMB policy and guidance by requiring DSMB oversight for, at a minimum, all randomized clinical trials of any phase that involve both investigator-masked interventions and enrollment of greater than 100 subjects. Additional factors that must be considered for designating other trials for DSMB oversight are long duration, complex design, high-risk interventions (e.g. genetic modification), vulnerable populations, and significant public health impact or high public interest and concern. NIAID divisions, the NIAID clinical director, or an institutional review board (IRB) may identify particular trials that require a DSMB.

DMID convenes a Safety Monitoring Committee (SMC), which is an independent group of experts that advises DMID and the study investigators for many Phase I and smaller Phase II trials, when it is determined that the DSMB is not required. The primary responsibility of the SMC is to monitor participant safety.

For certain clinical trials, DMID will require an Independent Safety Monitor (ISM) to be assigned for each study site and will be specified in the protocol. An ISM is a physician with relevant expertise whose primary responsibility is to provide to DMID an independent safety assessment in a timely fashion. Participation is for the duration of the DMID study and is a voluntary position that does not receive payment. The ISM must meet the requirements of the NIAID conflict of interest policy. The following clinical trials will generally require ISM(s):

  • Phase 0 clinical trials
  • Phase I clinical trials
  • Phase II clinical trials (expected to enroll 12 or more subjects per site, per year)

Conflict of Interest

DMID, in consultation with the study team, identifies committee members and approves them regarding their conflict of interest (COI) eligibility. The sources of these conflicts may be professional, financial, proprietary, or other personal interests in nature. DMID is responsible for deciding whether consultancies or the financial interests of the members materially affect their objectivity. DSMB/SMC Members and ISMs will notify DMID promptly if a change occurs that may create a potential conflict of interest.

Membership

The DSMB/SMC consists of at least three voting Members. A DSMB will include a biostatistician experienced in statistical methods for clinical trials and a clinician with relevant expertise; and although not required, a biostatistician may also be included in the SMC. Representatives of other clinical or laboratory specialties, bioethics, and the affected community are often critically important. When selecting DSMB/SMC Members, DMID should consider: clinical trials experience, relevant scientific expertise, prior DSMB/SMC service, and potential significant conflicts of interest. If needed, consultants may be invited to provide needed expertise, as ad-hoc members, and will not vote. NIAID employees will not serve as Members of the DSMB/SMC. Individuals who are directly involved in the conduct of the clinical trial will not be Members. Members will not be under the supervision of any of the investigators involved in the conduct of the clinical trial. Typically, the DSMB/SMC membership is for the duration of the clinical trial. If any Members leave the DSMB/SMC during the course of the trial, DMID will promptly appoint their replacement. If, in the judgment of DMID, a Member is not participating as needed in the DSMB/SMC activities, DMID will ask the Member to resign and will appoint a replacement. Membership in DMID DSMBs and SMCs is strictly voluntary as these positions do not receive compensation.

Responsibilities of the DSMB/SMC and DMID

The DSMB/SMC will be responsible for safeguarding the interests of the clinical trial subjects and for monitoring the overall conduct of the clinical trial.

The DSMB/SMC Members will

  • Sign a COI certification at the time they are asked to participate and provide updates to this information as needed
  • Provide updates to contact information to the DMID DSMB/SMC support contractor
  • Protect the confidentiality of the trial data and DSMB/SMC discussions
  • Review the protocol, template informed consent forms, study product information (e.g., Investigator’s Brochure and/or package insert), and plans for data safety and monitoring prior to initiation of the study
  • Approve the Charter
  • Review materials provided by DMID prior to the DSMB/SMC meetings
  • Periodically review and evaluate the accumulated study data for participant safety, study conduct and progress, and, when appropriate, efficacy
  • Review and evaluate ad hoc safety issues concerning the study at the request of DMID
  • Make recommendations to the DMID Medical Monitor (MM) and Clinical Project Manager (CPM) concerning continuation, termination, or modification of the study based on the observed beneficial or adverse effects of the study
  • Ensure review materials are kept secure. At the completion of the DSMB/SMC service, the Members will verify by email that the materials have been destroyed.
  • Participate in safety oversight for the period of the study conduct until notification is received from DMID that their service is complete

The DSMB/SMC chair will

  • Serve as the primary point of contact for the DSMB/SMC and facilitate meetings and discussions
  • Communicate the DSMB/SMC Recommendations to DMID immediately following the meeting
  • Work directly with the DMID DSMB/SMC support contractor (DMID-CROMS SOCS), which serves as the DSMB/SMC executive secretary to document recommendations and meeting summaries as well as provide signatures for these documents
  • Review, approve, and sign the Final Recommendations and meeting summaries immediately upon receipt from SOCS
  • Be available to DMID for consultation regarding potential safety or study-related issues such as reviewing an event that may meet a halting rule

DMID Clinical Project Manager and Medical Monitor

The DMID Clinical Project Manager (CPM) is the DMID primary point of contact responsible for the coordination and management of DMID-supported clinical research throughout the life cycle of the protocol. The DMID CPM will notify the DSMB/SMC Members, through the DMID DSMB/SMC support contractor, when their service is complete. The DMID Office of Clinical Research (OCRA) will assign a Medical Monitor (MM) to provide input on safety considerations during development of protocol and associated documents, and safety oversight throughout the life cycle of the clinical research including evaluation, assessment and monitoring of safety events and protocol deviations; participates in safety oversight committees, and consults with Independent Safety Monitors (ISMs).

DMID will identify DSMB/SMC Members and approve them based on their Conflict of Interest (COI) disclosure. The DMID CPM and MM will

  • Review and approve the SMC Charter
  • Determine the purpose for each meeting and ensure appropriate review materials are prepared for the SMC for each meeting
  • Review and approve Open session reports intended for all meeting participants
  • Participate in open sessions of meetings as DMID representatives
  • Review the SMC Recommendations and recommend actions for implementation by the study team, as applicable
  • Review and approve Open session meeting summaries

Meetings

DSMB/SMC committee meetings are primarily conducted via teleconference. The types of meetings convened are

  • Organizational Meeting An initial meeting of the DSMB/SMC will be held prior to any participant enrollment for the Members to
    • Review the Charter and the protocol
    • Review and approve the halting rules and planned safety monitoring for the study
    • Establish a meeting schedule including the estimated duration of safety oversight activities
    • Finalize format and protocol-specified statistical methods to be used in reports to be considered by the DSMB/SMC

    Note: The review of the protocol does not constitute participation in the design of the clinical trial, but rather gives the DSMB/SMC an opportunity to communicate to DMID any major issues or concerns that need to be addressed before the DSMB/SMC will assume oversight responsibilities.

  • Data Review Meetings

    Subsequent DSMB/SMC meetings will be held to review and discuss study data according to the schedule as described in the Charter. The purpose of the review is to evaluate safety and study conduct, and the study may be stopped because of significant safety concerns. Emerging efficacy data may be considered by the DSMB/SMC when evaluating the potential risks and benefits of the intervention under study.

  • Ad Hoc Meetings

    An ad hoc meeting is an unplanned meeting that is called for a specific purpose such as when a study halting rule is met. The meeting can be requested by any party with the responsibility of overseeing the trial (such as the PI, ISM, DSMB/SMC, DMID, industry collaborator). In the case of an ad hoc meeting, the DSMB/SMC may request special reports on an as-needed basis. These requests will be made to DMID, the unblinded statistician participating in the closed session or DMID-CROMS SOCS, as appropriate. The chair, in collaboration with DMID and DMID-CROMS SOCS, will schedule any unplanned meetings.

  • Final Meeting and End-of-Service

    Typically, the DSMB/SMC membership is for the duration of the clinical trial. However, it may not be practical to ask members to serve for many years due to extended long term follow up. In this case, it is recommended that the DSMB/SMC meet to review safety data while patients are receiving treatment and until the planned interim analyses for efficacy. After this, the DSMB/SMC would not meet unless DMID needed to consult with the DSMB/SMC due to a change in the protocol or the analysis that might affect the validity of the clinical trial.

At the conclusion of the final scheduled meeting, DMID-CROMS SOCS will confirm with the DSMB/SMC Members and DMID that no additional meetings are necessary. This usually indicates the end-of-service for most DSMBs/SMCs; however, this does not preclude contacting the Members to request the scheduling of an Ad hoc meeting in the case that DMID would like to consult with the DSMB/SMC, due to a potential safety concern or study related issue. DMID-CROMS SOCS will confirm with the CPM that end-of-service activities should proceed, notify the DSMB/SMC Members that their service is complete, provide them with Certificates of Appreciation on behalf of DMID, and request confirmation that they have destroyed all study-related documents.

Recommendations

At each meeting of the DSMB/SMC during the conduct of the trial, the DSMB/SMC will make a recommendation if the study should continue, be modified, or terminated. The DSMB/SMC may also provide recommendations relating to selection, recruitment and retention of subjects, their management, improving adherence to the protocol and procedures for data management and quality control. Immediately following the Closed session, a brief teleconference will be held between the DSMB/SMC Chair and the DMID CPM and MM to discuss the Recommendations of the DSMB/SMC. SOCS will prepare a brief written summary of the DSMB/SMC Recommendations. The Recommendations will be approved by the Chair and then forwarded to the DMID CPM and MM for their review and inclusion of action items for implementation, as indicated. If DMID determines not to implement a recommendation, a response with rationale will be provided to the DSMB/SMC. The final, signed Recommendation form will be distributed to the investigator(s), DSMB/SMC, DMID, and others as designated on the contact list upon receipt of signatures and will be posted on the DMID-CROMS Document Library.

Electronic Data Review

DSMB/SMC members may be asked to review data electronically and provide their assessment through email. Electronic reviews are conducted similarly to closed sessions in that electronic communications are limited to the members.

Contact: DMID-CROMS Safety Oversight Coordination Support (SOCS) is the DMID contractor that supports meeting conduct and related activities. DMID-CROMS SOCS serves as the executive secretary for the DSMB/SMC and supports the DSMB/SMC Chair in meeting conduct and documentation. SOCS may be contacted via email: SOCS@DMIDCROMS.com; telephone: 301-897-7455 or by fax: 800-275-7619. For international faxes, please use 301-897-1710.

NIAID Policies

DMID Policies

DMID Guidance and Tools

Additional Information

  • Selected References page​ under Data and Safety Monitoring for NIH, NIAID, and Food and Drug Administration policies and guidance ​​​
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Last Updated December 01, 2015