The FDA recently released draft guidelines for the use of data monitoring committees (DMCs) in clinical trials, “Use of Data Monitoring Committees in Clinical Trials.” When finalized, this guidance will replace the 2006 final guidance on the same topic entitled “Establishment and Operation of Clinical Trial Data Monitoring Committees.”
DMC[1] is a group of experts who review accumulated data from one or more ongoing clinical trials to monitor the ongoing safety of trial subjects and subjects not yet recruited into clinical trials. DMCs play a unique role in overseeing clinical trials because they are often the only group with access to open-label safety and efficacy data that accumulates during the conduct of a trial.
evolving landscape
In response to the expanded use of DMCs, FDA has resumed comment on the DMC guidance to provide stakeholders with an opportunity to help shape advice on how DMCs should operate. The 2024 Guidance differs from the 2006 Guidance in that it addresses “significant changes in the structure and practices of DMCs,” including:
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Increased use of DMCs in moderate-sized trials, as reflected in the ClinicalTrials.gov clinical trials databank
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DMC charters tend to be longer and more detailed
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Increasing use of DMCs to implement specific adaptive clinical trial designs
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Increased use of some DMCs to oversee entire clinical development programs (e.g., trials involving the same investigational product in different populations) rather than single clinical trials
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Potential enhancements to DMC.Example: For reviewing aggregate data for safety reporting of trials under an Investigational New Drug Application (IND).
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Globalization of medical product development and increasing use of multiregional clinical trials by DMCs
Additionally, FDA recognizes that several different groups and individuals may have or share responsibility for various aspects of clinical trial monitoring and oversight, and that all trial stakeholders (clinical It emphasizes the importance of clearly defining the roles of trial steering committees, endpoint evaluation/adjudication committees, etc. , and field/clinical surveillance teams).
When is DMC recommended?
FDA “strongly recommends” establishing a DMC when trial subjects are at risk of serious morbidity or mortality (e.g., hospitalization, heart attack, stroke, death). or if the investigational product has the potential to cause serious unexpected adverse events. However, the agency understands that FDA regulations rarely require DMC, and furthermore, it may not always be practical (e.g., clinical trials with rapid enrollment and short follow-up periods). ). Recognizing this, FDA requires sponsors to consider (a) the risks to trial participants and (b) whether a DMC is practical when deciding whether to establish a DMC. I advise you to do so.
For example, FDA recommends that sponsors consider using DMC when:
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There is prior information suggesting the potential for serious toxicity from the study treatment.
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Studies are large-scale, long-term, or multicenter.
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The subjects are vulnerable people.
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Experience in the therapeutic field is limited.
Strengthening recommendations regarding conflicts of interest
FDA maintains much of the advice in its 2006 guidance regarding potential conflicts of interest. The draft guidance continues to suggest that a conflict of interest may exist if a potential DMC member has a financial interest that could be materially affected by the trial results. . Involved in conducting research. or if you know that a potential member has strong views about the relative merits of a research intervention (referred to as an “intellectual conflict of interest”).
However, FDA has strengthened the language in its draft guidance regarding financial conflicts of interest for DMC members. In its 2006 guidance, the agency stated:
[We] Recommendation to These members Typically Does not have an ongoing financial relationship with the commercial sponsor of the clinical trial.[2]
In contrast, the new draft guidelines take a stricter and more definitive position regarding financial conflicts of interest.
In addition to compensation for serving on the committee, DMC members must have no ongoing financial relationship With commercial sponsors of clinical trials (or direct competitors)….[3]
Another notable addition to the draft guidance is FDA's declaration that a financial conflict of interest exists if an individual has an ongoing financial relationship with a “direct competitor” of the sponsor. be. The FDA defines a sponsor as a “direct competitor.” Be competitive in what is being evaluated. This latest information can have far-reaching implications for research in competitive fields or narrow disease areas.
Research sponsors establishing DMCs should be aware of these changes in FDA's position regarding conflicts of interest and carefully document their assessment of potential conflicts when selecting DMC members.
Other recommendations
Similar to the 2006 guidance, the 2024 draft guidance includes recommendations on:
- Composition of the DMC Committee. The draft guidance states that “appropriately structured procedures to identify unanticipated issues and to mitigate issues that may pose risks to subjects or adversely affect data quality or the integrity of the trial.'' “DMC should be provided.” To that end, we provide recommendations regarding DMC committee membership, conflict of interest issues, and training guidelines.
- Components of a Written Charter. FDA conducts all research based on a written charter that clearly describes the purpose of the DMC, the specific issues it is expected to address, and the recommendations it can make to sponsors during the trial. It specifies in detail how a DMC should operate. A DMC charter and written consent to the charter by all DMC members should be developed prior to conducting interim analyzes and ideally prior to trial initiation and subject enrollment. Government agencies may request a copy of the Charter.
- Responsibility of DMC. The draft guidance outlines how DMCs should consider a variety of matters related to the conduct of clinical trials, including clinical trial monitoring, interim data analysis, and monitoring of safety, efficacy, futility, and trial indications. ing.
- Intermediate data analysis. Recognizing the risk of research bias, FDA emphasizes the importance of confidentiality of interim data or interim data analyses, and in particular, the results of unblinded interim data and comparative interim analyzes are typically provided to DMC members or It emphasizes that it should not be accessible to anyone other than statisticians. Perform these analyses.
- Consideration of external data. When DMCs are asked to consider the influence of outside information on the trials they monitor, FDA warns that this can introduce study bias and requires sponsors to I advise you to be careful. An example of relevant external data would be the results of a relevant test (eg, a test of a pharmacologically relevant drug or equivalent device).
- Recommendations and documentation. FDA advises that DMCs should clearly state their recommendations to sponsors and keep minutes of all meetings, but use separate minutes for open and closed sessions. . The FDA says you have the right to request copies of these records when a trial is completed. Additionally, FDA has made it clear to sponsors that they need to analyze the motivations for DMC recommendations to ensure that they do not trigger reporting requirements (e.g., modification of a trial is not recommended for serious and unanticipated AEs). This may be based on the DMC's finding that the incidence of increased incidence in the Investigational Drug Division).
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FDA is seeking comments on this draft guidance until April 15, 2024. If you are interested in submitting comments or have questions about data monitoring boards or clinical trials in general, please contact your regular attorney at Hogan Lovells or any of the following: Author of this alert.