Randomized clinical trials are increasingly overseen by independent data monitoring committees (DMCs) that monitor trial conduct and safety and make recommendations for trial changes or closure. With the growing use of DMCs, several issues have emerged: 1. DMCs’ role and responsibilities vary greatly, leading to unclear expectations among stakeholders, 2. Challenges exist with effective communication between DMCs and other stakeholders, and 3. The need for and availability of DMC members is often misaligned, and there is no clear direction for preparing the next generation of DMC members. CTTI sought to clarify these issues and propose solutions to optimize DMC conduct.
Official CTTI recommendations address the role of the DMC, DMC composition, communication among DMC members and other stakeholders, the DMC charter, and issues related to DMC training.
The concept of DMCs was initially introduced in 1967 by the Greenberg Report to provide oversight to randomized clinical trials sponsored by the National Heart Institute. Among its recommendations is that trials should not be modified or terminated without the input from an independent group of scientists otherwise not involved in the conduct of the trial. Trials might be terminated because the intervention’s benefit was clearly established, there was sufficient evidence of harm, the trial was no longer viable or of interest, or some other compelling reason. The application of these recommendations in early NIH-sponsored cardiovascular trials led to the establishment of the independent data and safety monitoring board (DSMB) or more simply the Data Monitoring Committee (DMC). The charge to the DMC was to monitor trial conduct and safety and recommend trial changes or closure. Today, DMCs are used across therapeutic areas and may oversee single trials, groups of related trials, or the entire portfolio of research related to an investigational product. Membership of the independent DMCs may be internal to the trial sponsor, completely external or a mix, depending on the nature of the trial. Responsibilities may be limited to analyses of efficacy and safety, or expanded to include review of data quality and other trial operations. As use of DMCs has increased and evolved, critical issues have emerged, including the following:
Data Monitoring Committees (DMCs) (2014-ongoing)
DMCs composed of qualified members are convened for appropriate trials and conduct business in a way that is understood by all stakeholders and increases the quality of trial oversight.
To date, CTTI has completed the survey and focus groups and held an expert meeting. Results indicate that stakeholders from academia, industry, and government view the most important activity for DMCs to perform is to review both summary adverse events (AEs) and primary outcomes by treatment arm to assess the risk-benefit profile of an investigational product. According to responses, Phase 3 trials are more often reviewed by DMCs than other phases.
Focus groups were assembled to understand different perspectives on DMC use. The focus group comprised of DMC members felt that DMC roles should be dictated by a well-defined charter, they should have a limited role in the trial design to avoid potential investment/biases, and the committee should be provided unmasked treatment assignment data and have access to efficacy data. The focus group with FDA and IRB members indicated that the primary role of DMCs should be to conduct a detailed analysis of safety; however, this group felt that DMCs were overused. The industry sponsor focus group responded that DMCs are mainly employed in multicenter trials and RCTs that require DMCs; however, company policies vary.
Survey and focus group findings indicate that many sponsors have SOPs governing the conduct of DMCs and a DMC charter template that is tailored to each specific trial. Experts discussed the use of charters to communicate more clearly with DMCs. Specifically, that the charter should be the appropriate length, address DMC independence, pre-specify the planned contents of the DMC report, be clear but flexible about how decisions are to be made by the DMC, address trial blinding, and detail communication practice between all parties, including the frequency and format of meetings. While both the DMC and sponsor may benefit from close communication during charter development, interactions can be minimized once the charter is finalized so that DMCs can operate independently.
Experts also discussed the composition of DMCs, exploring the need for members to have different areas of expertise including ethics, statistics, and clinical or research experience in a particular therapeutic area. DMC members are identified via multiple different avenues. Qualifications for DMC membership should be more well-defined, and the DMC chair should be especially well-versed in clinical trials and have adequate previous experience with DMCs. Plans for future DMC members may include prospective training to better prepare them for DMC activities. The core curriculum should include didactic and interactive training sessions as well as an apprenticeship.
Presentations that describe findings are available here.
|Team Member||Jonathan Seltzer||ACI Clinical|
|Team Member||John Adler||AstraZeneca Pharmaceuticals LP|
|Team Member||Jason Connor||Berry Consultants|
|Project Manager||Annemarie Forrest||Clinical Trials Transformation Initiative|
|Team Member||Michael Pencina||Duke University|
|Team Leader||Karim Calis||Food and Drug Administration|
|Team Member||Robert Temple||Food and Drug Administration|
|Team Leader||Jane Perlmutter||Individual Patient/Caregiver|
|Team Leader||Raymond Bain||Merck & Co, Inc|
|Team Member||M. Khair Elzarrad||National Institutes of Health|
|Team Member||John McEachern||Parexel|
|Team Member||Miriam Donahue||Quintiles|
|Team Member||Roger Lewis||UCLA Harbor Medical Center|
|Team Member||Susan Ellenberg||University of Pennsylvania|
|Team Leader||David DeMets||University of Wisconsin|