http://www.fda.gov/RegulatoryInformation/Guidances/ucm127069.htm
Conflicts of interest deserve special consideration in choosing individuals to serve on a DMC. The most obvious conflict is financial interest that could be substantially affected by the outcome of the trial. (See Section 6 for further discussion. See also Department of Health and Human Services, Financial Relationships and Interests in Research Involving Human Subjects: Guidance for Human Subject Protection, available at >>http://www.hhs.gov/ohrp/humansubjects/finreltn/fguid.pdf.)
Investigators entering subjects into the trial have a different type of conflict of interest—their knowledge of interim results could influence their conduct of the trial. An investigator who is aware of early trends might change his or her pattern of recruitment, or modify his or her usual way of monitoring the status of participants. We therefore recommend that DMC members for a given trial not include investigators in that trial.
Individuals known to have strong views on the relative merits of the interventions under study may have an "intellectual" conflict of interest and might not be able to review the data in a fully objective manner; such individuals may therefore not be optimal DMC members. We recommend that sponsors avoid appointing to a DMC any individuals who have relationships with trial investigators or sponsor employees that could be considered reasonably likely to affect their objectivity.
We recommend that sponsors establish procedures to:
Assess potential conflicts of interest of proposed DMC members;
Ensure that those with serious conflicts of interest are not included on the DMC;
Provide disclosure to all DMC members of any potential conflicts that are not thought to impede objectivity and thus would not preclude service on the DMC;
Identify and disclose any concurrent service of any DMC member on other DMCs of the same, related or competing products.
The sponsor often appoints the DMC chair, but may seek advice from trial investigators or trial steering committee members. Prior DMC experience is more important for the chair than for other DMC members, as members will look to the chair for leadership on administrative as well as scientific issues. Sponsors will typically want to select a chair who is capable of facilitating discussion, integrating differing points of view, and moving toward consensus on recommendations to be provided to the sponsors. Sponsors may also want to be assured that a potential chair is willing to make a firm commitment to participate for the duration of the trial (or for the term of the appointment, for chairs of DMCs monitoring multiple trials).
4.2. Confidentiality of Interim Data and Analyses
As described in 21 CFR 314.126(b)(5) (drugs) and 21 CFR 860.7(f)(1) (devices), sponsors of well-controlled studies should take appropriate measures to minimize bias.3 Knowledge of unblinded interim comparisons from a clinical trial is generally not necessary for those conducting or sponsoring the trial; further, such knowledge can bias the outcome of the study by inappropriately influencing its continuing conduct or the plan of analyses. Unblinded interim data and the results of comparative interim analyses, therefore, should generally not be accessible by anyone other than DMC members or the statistician(s) performing these analyses and presenting them to the DMC (see id.). Consistent with 21 CFR 314.126(b)(5) (drugs) and 21 CFR 860.7(f)(1) (devices), sponsors should establish written procedures, which may be included in the DMC charter, to ensure the minimization of bias, such as maintaining confidentiality of the interim data (see Section 4.3.1.4). Sponsors may, of course, also address such confidentiality issues in written agreements between the sponsor and members of the DMC as well as written agreements between the sponsor and investigators.
Even for trials not conducted in a double-blind fashion, where investigators and patients are aware of individual treatment assignment and outcome at their sites, the summary evaluations of comparative unblinded treatment results across all participating centers would usually not be available to anyone other than the DMC. Section 6 addresses the particular confidentiality issues for the statistician/statistical team performing the interim analyses.
4.2.1. Interim Data
Interim comparative data, whether treatment assignment is revealed or coded, will be most securely protected from inadvertent or inappropriate access by the sponsor or its project team if the data are prepared for analysis by a statistical group that is independent of the sponsor and investigators—that is, the group is not otherwise involved in the trial design or conduct and has no financial or other important connections to the sponsor or other trial organizers (see Section 6). The lead investigators, the study steering committee, and/or the sponsor generally develop the analytical plan (often collaboratively), but problems can arise when these same individuals are involved in the actual preparation of the interim results, for reasons discussed in Section 6.4. They may, however, work with the statistician who will be preparing and presenting the interim analyses prior to the first analysis of unblinded data to develop a template for the interim reports. Procedures should be established to safeguard confidential interim data from the project team, investigators, sponsor representatives, or anyone else outside the DMC and the statistician(s) performing the interim analyses (see 21 CFR 314.126(b)(5) (drugs) and 21 CFR 860.7(f)(1) (devices)).
Although assigning responsibility for interim analysis to individuals employed by the sponsor is generally discouraged, such assignment may be appropriate if sufficiently secure procedures are in place to credibly ensure that the results of such analyses are not revealed to other sponsor employees or to anyone other than DMC members. We recommend that a description of such procedures be included in the DMC charter (see Section 4.3).
4.2.2. Interim Reports to the DMC
We recommend that any part of the interim report to the DMC that includes comparative effectiveness and safety data presented by study group, whether coded or completely unblinded, be available only to DMC members during the course of the trial, including any follow-up period—that is, until the trial is completed and the blind is broken for the sponsor and investigators. If interim reports are shared with the sponsor, it may become impossible for the sponsor to make potentially warranted changes in the trial design or analysis plan in an unbiased manner (see Section 6.3). Even aggregate data on safety and efficacy may be informative; these data may be needed for some trial management functions (e.g., sample size adjustments, centralized endpoint assessment), but are best limited to those who cannot otherwise carry out their trial management responsibilities.
In some cases (for example, in open-label trials with special concerns about safety), there may be a rationale for the sponsor and/or investigators to have access to the ongoing comparative safety data to ensure continuous monitoring. Such access should be specified and justified in the study protocol and understood by the DMC (see 21 CFR 314.126(b)(5) (drugs) and 21 CFR 860.7(f)(1) (devices)).
In many cases, the DMC receives reports in two parts: an "open" section, which presents data only in aggregate and focuses on trial conduct issues such as accrual and dropout rates, timeliness of data submission, eligibility rates and reasons for ineligibility; and a "closed" section, in which the comparative outcome data are presented. The open section of these reports is usually provided to sponsors, who may convey any relevant information in these reports to investigators, IRBs, and other interested parties, as the data presented in the "open" section are not likely to bias the future conduct of the trial and are often important for improving trial management.
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