INVESTIGATOR HELP:

It is important for the Investigator to have a written plan of how the collection of research data and the safety of research participants will be monitored. When designing a Data Safety and Monitoring Plan (DSMP), the investigator should take into consideration the type(s) of risk(s) the research involves. The DSMP should include (i) a general description of the DSMP; (ii) progress monitoring; (iii) reporting of adverse events or unanticipated problems involving risks to subjects or others; (iv) reporting of temporary or permanent suspensions to appropriate regulatory authorities; and (v) assurance of data accuracy and protocol compliance.

Reporting Adverse Events to the IRB Office when a Data Safety Monitoring Board (DSMB) is Designated for a Clinical Trial:
Investigators must identify the DSMB to the IRB Office (not members’ names), if any, that will be reviewing interim results, and include a brief description of the monitoring plan as well as procedures for transmitting the DSMB’s summary reports to the IRB Office. The Principal Investigator for multi site trials with DSMBs is expected to promptly forward to the IRB Office summary reports of adverse events that reveal unexpected non-serious and serious adverse events and other unexpected findings that affect the risk/benefit ratio. Such reports should also be referenced in the summary section of the IRBWise application for continuing review. The reporting of adverse events in the form of DSMB summaries, is in addition to, and does not replace, other reporting requirements of the IRB.

Continuing Review of DSMB-Monitored Clinical Trials:
When a multi-site clinical trial is subject to oversight by a Data Safety Monitoring Board (DSMB) whose responsibilities include review of adverse events, interim findings and relevant literature (e.g. DSMBs operating in accordance with the National Cancer Institute (NCI) Policy for Data and Safety Monitoring of Clinical Trials), the investigator may send a current statement from the DSMB indicating that it has reviewed study-wide adverse events, interim findings and any recent literature that may be relevant to the research, in submitting this information be submitted directly to the IRB. However, the IRB must still receive and review reports of local, on-site unanticipated problems involving risks to subjects or others and any other information needed to ensure that its continuing review is substantive and meaningful.

IRB POLICIES AND PROCEDURES:

IRB Policy 4.9 - Reporting of Adverse Events, Serious Adverse Events and Unanticipated Problems

It is the policy of the Department of Health (DOH) Institutional Review Board (IRB) to require reporting of unanticipated problems involving risks to participants or others and unexpected serious adverse events to the IRB.

IRB Policy 10.1 - IRB Compliance Activities

It is the policy of the Department of Health (DOH) Institutional Review Board (IRB) to oversee internal and local compliance reviews and/or auditing efforts, as it deems necessary, in order to assure the protection of human research participants and compliance with federal regulations, state and local law as well as DOH IRB policies and DOH's Federal Wide Assurance with OHRP.

FEDERAL REGULATIONS/GUIDANCE:

OHRP Guidance on Continuing Reviews:
WHAT ARE SOME ADDITIONAL CONSIDERATIONS FOR CONTINUING
REVIEW IN MULTI-CENTER TRIALS MONITORED
BY A DSMB, DMC, OTHER SIMILAR BODY, OR SPONSOR?

Continuing review of research by the IRB should include consideration of adverse events, interim findings, and any recent literature that may be relevant to the research.

OHRP recognizes that such information may not be readily available to local investigators participating in multi-center clinical trials or to their local IRBs. However, OHRP notes that such trials are often subject to oversight by a Data and Safety Monitoring Board (DSMB), Data Monitoring Committee (DMC), other similar body, or sponsor whose responsibilities include review of adverse events, interim findings, and relevant literature.

In such circumstances, IRBs conducting continuing review of research may rely on a current statement from the DSMB or sponsor indicating that it has reviewed study-wide adverse events, interim findings, and any recent literature that may be relevant to the research, in lieu of requiring that this information be submitted directly to the IRB. The IRB must still receive and review reports of local, on-site adverse events and unanticipated problems involving risks to subjects or others and any other information needed to ensure that its continuing review is substantive and meaningful. In addition, institutions and IRBs may require additional information for continuing review at their discretion.

POLICY OF THE NATIONAL CANCER INSTITUTE
FOR DATA AND SAFETY MONITORING
OF CLINICAL TRIALS

Introduction

All clinical trials supported or performed by NCI require some form of monitoring. The method and degree of monitoring should be commensurate with the degree of risk involved in participation and the size and complexity of the clinical trial. Monitoring exists on a continuum from monitoring by the principal investigator/project manager or NCI program staff to a data and safety monitoring board (DSMB). These monitoring activities are distinct from the requirement for study review and approval by an Institutional Review Board (IRB).

Throughout this policy, the term "awardee" means the awardee institution. In the case of NCI intramural research, the comparable institutional unit is the NCI.

Responsibility for Data and Safety Monitoring

Responsibility for data and safety monitoring depends on the phase of the study and may be conducted by NCI program staff or contractor, by the principal investigator/project manager conducting the study, or by a DSMB. Regardless of the method used, monitoring must be performed on a regular basis. Oversight of the monitoring activity is the responsibility of NCI program staff. In the case of extramurally funded research, adherence to this NCI policy and any data and safety monitoring policies of the NCI Division making the award will be made a condition of the award.

Phase I and Phase II studies may be monitored by the principal investigator/project manager, by NCI program staff or a designee, or jointly. When conducted by the principal investigator/project manager, the awardee must have written policies and procedures describing the monitoring and reporting processes in place. The awardee's policies must be consistent with any policies of the NCI Division making the award. NCI program staff from the awarding NCI division will determine the acceptability of the awardee's policies and procedures. These will be documented in the grant, cooperative agreement or contract file and become part of the award.

All Phase III randomized clinical trials supported or performed by NCI require monitoring by a DSMB. The organization, responsibilities, and operation of the DSMB are described below.

For studies co-funded with other NIH Institutes or Centers (IC), the lead NIH IC will be responsible for monitoring the study and establishing a DSMB if necessary. Oversight of the DSMB will be the collaborative responsibility of the lead NIH IC and NCI.

Requirement for Data and Safety Monitoring Boards

Data and Safety Monitoring Boards must be established to monitor all Phase III randomized clinical trials supported or performed by NCI. Funds to support the functions and operations of the DSMBs will be provided by NCI in a fashion to be determined by each NCI Division.

Responsibilities of the DSMB

1. Familiarize themselves with the research protocol(s) and plans for data and safety monitoring.
2. Review interim analyses of outcome data and cumulative toxicity data summaries to determine whether the trial should continue as originally designed, should be changed, or should be terminated based on these data. The DSMB reviews trial performance information such as accrual information. The DSMB also determines whether and to whom outcome results should be released prior to the reporting of study results.
3. Review reports of related studies to determine whether the monitored study needs to be changed or terminated.
4. Review major proposed modifications to the study prior to their implementation (e.g., termination, dropping an arm based on toxicity results or other reported trial outcomes, increasing target sample size).
5. Following each DSMB meeting, provide the study leadership with written information concerning findings for the trial as a whole related to cumulative toxicities observed and any relevant recommendations related to continuing, changing, or terminating the trial. A copy of this information will be provided to the NCI Division Director or designee. The study leadership will provide information on cumulative toxicities and relevant recommendations to the local principal investigators to be shared with their IRBs.

Membership

The DSMB voting members will be appointed for a fixed term by the principal investigator/project manager or designee. Proposed DSMB members must be reviewed and approved by the awarding NCI Division Director or designee prior to their appointment. The Chair of the DSMB will be selected from among the voting members. Voting members of the DSMB should include physicians, statisticians, other scientists, and lay representatives selected based on their experience, reputation for objectivity, absence of conflicts of interest (and the appearance of same), and knowledge of clinical trial methodology. Program and statistical staff from the NCI will be permitted to serve as non-voting ex officio members of the DSMB at the request of the NCI Program Director.

Voting members may be from within or outside the institution1, but a majority should not be affiliated with the institution. Staff affiliated with the institution who are members of the DSMB should view themselves as representing the interest of patients and not that of the institution. Voting members directly involved with the conceptual design or analysis of a particular trial must excuse themselves from all DSMB discussion of the particular trial and must not receive that portion of the DSMB report related to the particular trial.

Meetings

DSMB meetings will be held at least annually and more often depending on the nature and volume of the trials being monitored. Each meeting should be divided into three parts. First, an open session in which members of the clinical trial team may be present, at the request of the DSMB, to review the conduct of the trial and to answer questions from members of the DSMB. The focus in the open session may be on accrual, protocol compliance, and general toxicity issues. Outcome results must not be discussed during this session. Following this session, a closed session involving the DSMB members and the coordinating center/statistical office statistician(s) handling the trial should be held. The statistician(s) should present and discuss the outcome results with the DSMB. A final executive session involving only DSMB members should be held to allow the DSMB opportunity to discuss the general conduct of the trial and all outcome results, including toxicities and adverse events, develop recommendations, and take votes as necessary.

A written report containing the current status of each trial monitored, and when appropriate any toxicity and outcome data, should be sent to DSMB members by the coordinating center/statistical office allowing sufficient time for the DSMB members to review the report prior to the meeting. This report should address specific toxicity concerns as well as concerns about the conduct of the trial. The report may contain recommendations for consideration by the DSMB concerning whether to close the trial, report the results, or continue accrual or follow up.

Recommendations from the DSMB

DSMB recommendations should be based on results for the trials being monitored as well as on data available to the DSMB from other studies. It is the responsibility of the coordinating center/statistical office, trial investigator(s), NCI program staff and statisticians, and individual DSMB members to ensure that the DSMB is kept apprised of non-confidential results from other related studies that become available, and of any programmatic concerns related to trials being monitored. It is the responsibility of the DSMB to determine the extent to which this information is relevant to its decisions related to specific trials.

DSMB recommendation(s) will be given to the trial principal investigator/project manager2 with a copy provided to the NCI Division Director or designee. If the DSMB recommends a study change for patient safety or efficacy reasons, or that a study be closed early due to slow accrual, the trial principal investigator/project manager must act to implement the change as expeditiously as possible. In the unlikely situation that the trial principal investigator/project manager does not concur with the DSMB, then the NCI Division Director or designee must be informed of the reason for disagreement. The trial principal investigator/project manager, DSMB Chair, and the NCI Division Director or designee will be responsible for reaching a mutually acceptable decision about the study. Confidentiality must be maintained during these discussions. However, in some cases, relevant data may be shared with other selected trial investigators and NCI staff to seek advice to assist in reaching a mutually acceptable decision.

If a recommendation is made to change a trial for other than patient safety or efficacy reasons or for slow accrual, the DSMB will provide an adequate rationale for its decision. In the absence of disagreement, policies of the NCI Division that made the award under which the trial is supported should be followed in regard to amending the protocol or changing the award.

Release of Outcome Data

In general, outcome data should not be made available to individuals outside of the DSMB until accrual has been completed and all patients have completed their treatment. At this time, the DSMB may approve the release of outcome data on a confidential basis to the trial principal investigator/project manager for planning the preparation of manuscripts and/or to a small number of other investigators for purposes of planning future trials. Any release of outcome data prior to the DSMB's recommendation for general dissemination of results must be reviewed and approved by the DSMB.

Confidentiality Procedures

No communication, either written or oral, of the deliberations or recommendations of the DSMB will be made outside of the DSMB except as provided for in this policy. Outcome results are strictly confidential and must not be divulged to any non-member of the DSMB, except as indicated above in the Recommendations section, until the recommendation to release the results are accepted and implemented. Each member of the DSMB, including non-voting members, must sign a statement of confidentiality.

Conflict of Interest

DSMB members are subject to the awardee's policies regarding standards of conduct. Individuals invited to serve on the DSMB as either voting or non-voting members will disclose any potential conflicts of interest, whether real or perceived, to the trial principal investigator/project manger and the appropriate institutional officials(s), in accordance with the institution's policies. Conflict of interest can include professional interest4, proprietary interest, and miscellaneous interest as described in the NIH Grants Policy Statement, Page II-12, and 45 CFR Part 94. Potential conflicts which develop during a member's tenure on a DSMB must also be disclosed. Decisions concerning whether individuals with potential conflicts of interest or the appearance of conflicts of interest may participate in a DSMB will be made in accordance with the institution's policies.