1.        Introduction

ECOG procedures for monitoring phase III trials were developed in accordance with the NCI Cooperative Group Data Monitoring Committee Policy (3/12/07), available at http://ctep.cancer.gov/monitoring/index.html. A single Data Monitoring Committee (DMC) is responsible for monitoring all phase III and selected phase II studies (including all randomized phase II cancer prevention and control studies) led by ECOG. The structure and voting membership of the DMC ensure that critical decisions that are made while the results of a randomized trial are still blinded are free of conflicts of interest.

The guidelines below specify the DMC's authority for acting, its responsibilities, its membership, and the general procedures the committee follows. The scientific direction of the Group's disease committees is the responsibility of the individual study chairs, the disease committee chairs, and, ultimately, the Group Chair. The timing of scientific reporting and the planning of a research program is the unique responsibility of these ECOG members and must be defended at peer review.

It is ECOG policy that no treatment-specific outcome results (even in blinded or coded form) be made public while a phase III trial is still accruing patients. Except in rare studies requiring treatment over extended periods, outcome results remain confidential while patients continue to receive protocol treatment. For open-label studies, unblinded interim toxicity data are generally published in the semiannual updates for the ECOG Group Meetings. For studies with blinded treatments, generally only pooled toxicity data are released to the investigators and published in the semi-annual reports while the study is underway, and only the DMC has access to toxicity data by arm. This policy preserves the necessary confidentiality of outcome-related data in a trial while allowing participating physicians to learn of frequently encountered side effects.

2.        Authority

The ECOG Data Monitoring Committee is an advisory committee to the Group Chair. The DMC makes recommendations to the Group Chair, who can approve or disapprove the recommendations, as described below.

3.        Responsibilities

The ECOG DMC is responsible for:

1.     Reviewing interim toxicity data for a trial and proposing corrective actions when the side effects for one or more treatments in a trial are unexpectedly severe. These corrective actions may include modifications to one or more treatments, early closure or suspension of the trial or of one or more of the treatment arms, or limiting participation in the trial to a subset of ECOG institutions or a subset of the original patient population. This review of toxicity by the DMC is in addition to that of the study chair and study team, who have primary responsibility for monitoring toxicity.

2.     Reviewing interim analyses of outcome data and recommending changes in the study status on the basis of these analyses. These changes in status may include early termination of accrual and release of results consistent with any sequential stopping rules used in the design of the study or, in the case of events unforeseen at the design stage, consistent with statistical principles for early stopping of phase III trials. Changes may also include increases to the accrual goal or major changes to the eligibility criteria for the trial.

3.     Reviewing proposed major modifications to the study (including any changes to the sample size, primary analysis, or interim monitoring) prior to their implementation. Major modifications to the study design that are not motivated by confidential outcome data or patient safety/toxicity data (e.g., increasing the sample size because of faster-than-expected accrual) must be discussed with NCI's Cancer Therapy Evaluation Program (CTEP), and CTEP must indicate their willingness to approve the change before it can be presented to the DMC for consideration.

4.     Assessing the impact of independent scientific investigations, especially other trials, on the trial being monitored and recommending changes based on those external results.

5.     Reviewing requests for release or use of study outcome data. Any release of study outcome data outside the DMC, including release within ECOG or to NCI personnel not members of the DMC, prior to the final approval for general dissemination of results, must be reviewed and recommended for approval by the DMC. Such requests include the following:

a.      Requests for clinical information, such as baseline characteristics or secondary outcomes, for publication or presentation of laboratory data or other nontherapeutic data from any patients accrued to the phase III trial. The DMC review of these requests will not be confined to the cycle of regularly scheduled DMC meetings, but will be ongoing, to accommodate abstract and grant deadlines and manuscripts in preparation.

b.     Requests for data from sponsoring organizations.

c.      Requests from disease committee chairs and prospective study chairs for confidential access to interim results to aid in planning future studies. The DMC considers each request based on the importance and usefulness of the requested information and the potential risk to the integrity of the study. Access to interim outcome results is granted only rarely while patients remain on protocol treatment. After most patients have completed protocol therapy, the risk to the study is usually small, and access is allowed more routinely.

These responsibilities end after the full study results have been released. The DMC would usually not be involved in further review of the trial after that time, but the Group may consult the DMC at any time on other issues, such as appropriate action for late toxicities.

The scientific responsibilities for publishing or presenting the results of a trial to the scientific community and for using the results of a trial for planning future ECOG studies, following release of data by the DMC, continues to lie with the study chair, study statistician, and disease committee chair.

4.        Membership

The ECOG DMC consists of nine voting members and six nonvoting members. The voting members are appointed by the ECOG Group Chair with the approval of the CTEP Associate Director or his/her designee. At least five of the voting members are from outside ECOG and have no other affiliation with the Group. At least one outside member is a biostatistician, and at least one member is a cancer survivor. The other voting members are selected to provide expertise in medical oncology, hematology, cancer therapy modalities, and biostatistics. Per CTEP policy, no member of the executive leadership of ECOG or any other Cooperative Group may serve on the DMC.

The six nonvoting members are the ECOG Group Statistician, the DMC coordinating statistician, an ECOG staff member, two representatives (normally a clinician and a statistician) from the Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, of the National Cancer Institute (NCI), and one representative from the Division of Cancer Prevention of the NCI. The Group Statistician may at his/her discretion also perform the role of the DMC coordinating statistician, in which case there would not be a second nonvoting member from the Statistical Center. The ECOG staff member helps with administrative aspects of the meeting, such as taking notes and preparing the report of recommendations for the Group Chair.

Any member of the ECOG DMC who is a member of the study team for a trial under DMC consideration must recuse himself or herself from all aspects of the monitoring of that trial. (The study team includes the study chair, co-chair, statistician, and disease committee chair, as listed on the face page of the study.) The Group Chair may expand the voting membership of the DMC for any particular phase III trial if special expertise is required or if a voting member is a member of the study team.

The voting members of the DMC are appointed to four-year terms. DMC members may be reappointed at the discretion of the Group Chair. Terms are staggered so that no more than three terms end in any one calendar year. The DMC chair is appointed by the ECOG Group Chair from among the voting members.

Members who fail to attend two consecutive meetings (including conference calls) may be replaced. DMC members sign confidentiality agreements at each DMC meeting. Any member (voting or nonvoting) who violates confidentiality of the DMC deliberations will be removed from the committee.

Individuals serving as voting or nonvoting members of the DMC must disclose to the Group Chair any potential real or perceived conflicts of interest. These potential conflicts include professional, proprietary, financial, or miscellaneous interest considerations as described in the CTEP Conflict of Interest Policy for Cooperative Group Phase 3 Trials. The Group Chair, with the advice of an ad-hoc committee, reviews possible conflicts and determine whether there is sufficient basis to exclude the individual from serving on the DMC. Potential conflicts that develop during the conduct of a trial should also be disclosed to the Group Chair. To facilitate this disclosure, all DMC members must complete ECOG conflict of interest forms annually.

5.        Procedures

The ECOG Data Monitoring Committee meets at least twice each year. Meetings to review all studies currently being monitored by the DMC are scheduled 2-8 weeks before each ECOG semiannual meeting. Meetings are ordinarily held in person. However, if the DMC chair and the DMC coordinating statistician agree that the agenda for the meeting is sufficiently light, then the meeting can be held by teleconference. Per NCI policy, meetings must be held in person at least once every 18 months; exceptions to this must be approved by CTEP.

Reports on accrual, case status, toxicity, progress toward scheduled interim analyses, outcome data (when appropriate), and any other issues of potential concern, are prepared prior to the meeting by the study statisticians on all studies monitored by the DMC. The database cut-off for planned interim outcome analyses will be 8 weeks prior to the scheduled date of the DMC meeting. These reports are circulated to the DMC approximately three weeks before the meeting. Any member of the committee may request additional data after seeing the report, but such requests must first be approved by the DMC coordinating statistician or the DMC chair.

Before the meeting, the DMC coordinating statistician and the DMC chair review the reports and recommend a list of studies to be formally discussed by the DMC. A study will also be discussed if requested by any other member of the DMC.

A study chair, study statistician, the Group Chair, or the Group Statistician may also request that a phase III study be discussed at any time. If circumstances require that a study be discussed other than at the regularly scheduled times, the committee may meet in person or by conference call at the discretion of the DMC chair.

At the DMC meeting, there is an open session, which may include a presentation on clinical issues, accrual, compliance, and toxicity by the study statistician, study chair, and/or scientific committee chair. CTEP/NCI staff not on the DMC may be present to answer questions during the open session at the request of the DMC. Outcome data will be presented in a closed session by the study statistician; neither the study chair, committee chair, nor other members of the study team may be present for this discussion. There is also an executive session for formulating recommendations; this executive session includes only voting and nonvoting members of the DMC and excludes any members of the study team.

Any recommendations regarding a study must be approved by a majority vote of the voting DMC members present in the executive session.

All deliberations of the DMC are confidential, and all recommendations transmitted to the Group Chair must be considered confidential until implemented by the Group Chair. Any member who violates the confidentiality of the committee will be removed by the Group Chair. Any study chair who violates that confidentiality will be removed as study chair of that trial.

6.        Recommendations

The DMC recommendations will be communicated to the Group Chair by the DMC coordinating statistician as quickly as possible following the DMC meeting. In the event a change to a protocol is recommended by the DMC, the Group Chair may seek the advice of the study chair, disease committee chair, and/or Group Statistician in a confidential manner. In considering recommendations for release of data, the Group Chair also needs to take into account any binding data exclusivity agreements that ECOG or CTEP has with a company collaborator or other entity.

1.     In the event that the DMC recommends a study change for patient safety reasons (including early stopping of inferior therapy), the Group Chair will act to implement the change as expeditiously as possible. For studies that are being closed, although CTEP pre-approval is not required, the Group Chair (or his/her designee) will inform and discuss the closure of the study with the responsible NCI Program Director or his/her designee before disclosing the study closure to anyone. In the unlikely situation that the Group Chair does not concur with the DMC recommendation, the CTEP Associate Director must be informed of the DMC's recommendation and the Group Chair's reasons for disagreeing with the recommendation. The CTEP Associate Director and the Group Chair, in consultation with the DMC chair, will be responsible for reaching a mutually acceptable decision about the study. Confidentiality will be maintained during these discussions, but relevant data will be shared with the Group Chair, CTEP Associate Director, and other parties whom they wish to involve in reaching a decision.

2.     In the event that the DMC recommends a study be closed early due to slow accrual, provided that the CTEP members of the DMC have been previously informed of this possibility, then the recommendation of the DMC is processed as described in item 1 above.

Note: CTEP may have additional closure policies that apply to studies with slow accrual that have not yet had formal interim efficacy analyses presented to the DMC.

3.     In the event that the DMC recommends a change in a study for reasons other than patient safety or study closure due to slow accrual (e.g., to extend accrual because of a lower-than-expected event rate), the DMC provides an adequate rationale to the Group Chair. If the Group Chair agrees with the recommendations, the Group Chair is responsible for having an amendment prepared to reflect the recommendations of the DMC and provides the rationale for the changes. The amendment is submitted to CTEP, and CTEP approval is required before implementation of the change, although it is anticipated that a decision to override the DMC's recommendation would be made only in the most exceptional circumstances.

For DMC recommendations specific to cancer prevention and control trials funded by a CCOP Research Base grant, the appropriate NCI staff to include and report to are the DCP/COPTRG Program Director (instead of the CTEP physician member of the DMC), the Chief of COPRTRG (instead of the NCI Program Director) and the Associate Director for Clinical Research in DCP (instead of the CTEP Associate Director).

7.        Confidentiality Procedures

No communication of the deliberations or recommendations of the committee, either written or oral, should be made outside of the committee except as provided for in these policies and procedures. Statements of confidentiality shall be signed by all DMC members. Outcome (efficacy) results are strictly confidential and must not be divulged to any non-member of the DMC (excepting the Group Chair and NCI staff as described above) without the approval of the DMC until the recommendation to report the results is accepted and implemented.

8.        Intergroup Trials

These guidelines apply also to intergroup trials. The DMC of the group whose statistical center is coordinating the trial is responsible for monitoring the trial. In such cases, the term 'Group Chair' in this document applies to the Chair of the coordinating group.

9.        Institutional Review Board Requirements

The National Institutes of Health (NIH) requires that summaries of safety data be provided to the local institution's institutional review board (IRB) for all studies that are monitored by a DMC. In ECOG, safety summaries take the form of toxicity tables in the agenda reports of the Group Meetings. Copies of the reports are provided to the IRB.

Reports of the DMC meetings must also be provided to institutional IRBs to document that a review of data and outcomes took place on a given date, to summarize the DMC's review of cumulative toxicities reported from all participating sites, and to inform investigators of the DMC's conclusions regarding the progress and modification of studies. Following the final resolution of recommendations, the reports are available online to ECOG members. (Access requires an ECOG member user name and password.) Local investigators are responsible for providing the reports to their IRB.

10.        Document Revision History

11.        Document Reviewers

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