By Jessie L. Bekker

The U.S. Food & Drug Administration (FDA) released new proposed draft guidance in February that would change the FDA’s outlook on the engagement of a data monitoring committee (DMC) in clinical trials.

A DMC, also often referred to as a data and safety monitoring board or an independent data monitoring committee, consists of individuals with specialized knowledge who review emerging data from an ongoing trial to determine whether the trial should be modified, continued or stopped. The FDA recommended in its 2006 Guidance titled “Guidance for Clinical Trial Sponsors: Establishment and Operation of Clinical Trial Data Monitoring Committees” the use of DMCs  “in situations in which safety concerns may be unusually high” (for example, where treatment administration is particularly difficult, the study population was inherently vulnerable or the study was performed in high morbidity or mortality populations). Historically, DMCs were used in large, randomized, multicenter trials sponsored by federal agencies, like the National Institutes of Health (NIH). However, in recent years, study sponsors have employed DMCs in new categories; now, DMCs may oversee modestly sized trials to entire clinical development programs, rather than a single trial. While optional in these settings, DMCs are required for use in emergency research where informed consent is not obtained from all research subjects.

Below is a summary of the draft guidance, including considerations in determining whether to use a DMC, the DMC’s relationship to other clinical trial groups, like Institutional Review Boards (IRB), and operational considerations when employing a DMC.

When to Establish a DMC

The FDA’s new draft guidance specifically notes that DMCs are not appropriate for use in all clinical trial settings. For example, DMCs might be impractical for short-term trials, while the FDA highly recommends their use when trial subjects are at serious morbidity or mortality risk, or where causality assessment is based on single risk factor.

DMCs Compared to Other Review Groups

DMCs, unlike other review groups, are “the only oversight group that has access to accumulating unblinded safety and efficacy data.” The FDA’s guidance foresees a DMC’s interactions with other trial review groups as follows:

IRB. While an IRB is responsible for evaluating a trial to determine whether risks to subjects are minimized and such risks are “reasonable in relation to anticipated benefits,” an IRB typically only reviews blinded data and significant new information about a trial.

Clinical Trial Steering Committees. Steering committees take on several roles, including recruitment and loss to follow-up and demographic inclusion, but like an IRB, typically only reviews blinded data. Where a steering committee and a DMC are used, the FDA recommends a clear delineation between each respective group’s roles and responsibilities in the study.

Other Committees. The FDA’s guidance document describes the recommended relationship between a DMC and other types of reviewing bodies, like endpoint assessment committees, clinical site monitors, safety data review entities and adaptation committees. For example, endpoint assessment committees should not review unblinded data, and therefore, should be separate and distinct from the DMC, while safety data review entities should not review efficacy data, a role generally assumed by a DMC.

DMC Composition. The FDA’s guidance notes that a DMC should be established by a sponsor, trial steering committee or both. DMCs are generally comprised of experts in the field of research, including clinicians, biostatisticians, experts in informatics and technology, FDA regulatory experts, and those with DMC experience. Independent statisticians should also perform statistical analyses, though these statisticians should not serve on the DMC in a voting capacity. Per the FDA, “a well-constructed DMC should be equipped to identify unexpected issues and mitigate problems that could otherwise cause risks to subjects or could adversely affect the quality of the data and integrity of the trial” (emphasis added). Moreover, financial and intellectual conflicts of interest should be evaluated, and those who could bias the trial results eliminated from consideration. In a separate section, the FDA outlines the need for independence of the DMC and its members from the study sponsor.

DMC Charter. The FDA’s recommendation includes a list of items to be included on a DMC’s written charter, which should state the purpose of the DMC, its specific goals and the possible recommendations it might make to the study’s sponsor. The FDA’s guidance sets forth several elements of a complete charter, including the DMC composition, meeting criteria, the DMC’s planned analyses and data confidentiality.

DMC Responsibilities. The FDA sets forth a detailed list of responsibilities a DMC should assume. Broad categories include monitoring: (1) trial conduct, like recruitment rates and participant dropout and the completeness and timeliness of data; (2) results of interim data analyses; and (3) safety, effectiveness, trial futility and the need for trial adaptations. The DMC may also consider external data and make recommendations to the sponsor concerning continuation of the trial.

FDA Reporting. Finally, although the FDA requires that study sponsors report to the FDA findings that a reasonable possibility of serious unanticipated adverse events was tied to the drug’s use, the FDA’s recommendation would also ask sponsors to inform the FDA about all of the DMC’s safety-related recommendations, whether or not serious.

While the draft guidance, if implemented, would supersede the 2006 guidance, its terms would constitute nonbinding recommendations. The FDA is accepting public comments to its draft guidance until April 15, 2024. A copy of the draft guidance can be reviewed by visiting https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-data-monitoring-committees-clinical-trials.

Jessie Bekker is an attorney at Burr & Forman practicing exclusively in the healthcare practice group. Jessie may be reached at (205) 458-5275 or jbekker@burr.com.