While FDA regulations require sponsors to monitor their trials, there are different ways this can be accomplished. One method is an independent DMC, sometimes also referred to as a Data and Safety Monitoring Board (DSMB). All trials must have a data monitoring plan, but not all trials need a DMC. Current U.S. Food and Drug Administration (FDA) regulations impose no requirements for the use of DMCs except for research studies conducted in emergency settings in which the requirement for informed consent has been waived (21 CFR 50.24(a)(7)(iv)). Funding agencies impose broader requirements, as discussed later.
FDA guidance advises considering the following when determining whether a study warrants the use of a DMC:
- Is it a large, multicenter study of long duration?
- Is the study endpoint such that a finding at interim analysis might ethically require termination of the study before its planned completion?
- Are there a priori reasons for a particular safety concern (e.g., particularly invasive treatment?)
- Is there prior information suggesting the potential for serious toxicity due to the study treatment?
- Is the study being performed in potentially fragile or vulnerable populations (e.g., children, pregnant women, very elderly, terminally ill, those with diminished mental capacity)?
- Is the study being performed in a population at elevated risk of death or other serious outcomes, even when the study objective addresses a lesser endpoint?
If a study has one or more of these characteristics, it is recommended that sponsors consider the use of a DMC to further protect study participants.
Additional considerations include whether review by a DMC is practical (e.g., due to study length) and whether a DMC can help ensure the scientific validity of a trial. Examples of studies that may not need a DMC include short-term studies where a DMC is unlikely to have the opportunity to make a difference and studies with less serious outcomes (e.g., symptom relief) in which early termination is unlikely to be appropriate. As many PCTs will be large, multicenter studies with serious clinical outcomes, it is likely that most of these will warrant use of a DMC (Ellenberg et al. 2015).
Research sponsors may have their own policies outlining the type of data monitoring required and which studies must have a DMC. For example:
- NIH policy requires NIH-funded trials to have a DMC if they are multicenter and pose a risk to participants.
- PCORI policy states that a DMC should be appointed if required by the IRB, regulatory agency, or determined appropriate “after considering factors such as potential risks; target study subject population, nature, and size; and the research project’s scope and complexity.”
PCT investigators should work with their sponsor(s) to determine whether a DMC will be used, as well as to develop and implement an appropriate data monitoring plan for the study. The NIH Collaboratory has made available brief descriptions of the data monitoring plans for all NIH Collaboratory Demonstration Projects as part of the publicly available ethical and regulatory descriptions for these trials. The data monitoring details are excerpted in the table below. Not all NIH Collaboratory PCTs are using an independent DMC, but all have a data monitoring plan that was discussed with the NIH sponsor and determined to be in compliance with their policies. More details on data monitoring for some of these trials will be explored throughout the chapter.
Data Monitoring Plans Used in NIH Collaboratory PCTs
|Demonstration Project||Minimal risk?||Uses a DMC?||Monitoring plan|
|PPACT||Yes||No||An independent monitor identified by the study team and sponsor reviews subject accrual, serious adverse events, and clinician/patient compliance with treatment every 6 months.|
|LIRE||Yes||No||Two safety officers review study data at regular intervals for any safety concerns. Safety endpoints are emergency department visits within 90 days of index image and death within 6 months|
|ABATE Infection||Yes||No||The sponsor approved the trial’s data monitoring plan, and study-related event forms were distributed to all participating sites.|
|SPOT||Yes||Yes||Negotiating the terms and procedures for DMC monitoring was a major barrier leading to significant delay and extra expense.|
|STOP CRC||Yes||No||While a full DMC was not required, independent monitoring was determined to be appropriate. The trial’s data and safety monitoring plan consists of semi-annual review of study progress and adverse events by two independent monitors (a statistician and a gastroenterologist) who were approved by the sponsor.|
|TiME||Yes||Yes||The DMC has the authority to make formal recommendations to the sponsor about early termination of the trial for futility, efficacy, or safety.|
|TSOS||Yes||Yes||Outcomes monitored include adverse events (medication side effects, death), suicidality, loss to follow-up, and demographics.|
|ICD-Pieces||Yes||Yes||The study team tracks safety events, including the primary outcome (all-cause unplanned hospitalization), secondary outcomes (cardiovascular events, emergency department visits, and death), and safety events that are possible outcomes of the interventions (such as hypotension and hyperkalemia). The team regularly informs the DMC of these safety events. There are no plans for a formal interim analysis. The study team tracks the primary outcome rates by healthcare system and reports these to the sponsor and DMC quarterly. The study team and the NIH will review the intraclass correlation coefficient and recruitment goals based on the most updated data.|
|PROVEN||Yes||Yes||The study team prepares formal data reports for the DMC biannual meetings, as well as ad hoc reports as requested. The statisticians are able to review unblinded interim data, but the PIs remain blinded.|
Source: Demonstration Project ethics and regulatory documentation. For more information on the Demonstration Projects, including study population and primary outcome, see the Demonstration Projects table in the What Is a Pragmatic Clinical Trial chapter.
In sections that follow, we review special considerations for data monitoring in PCTs, including monitoring protocol adherence when information on “real-world” use is desired, issues associated with use of EHR data such as data quality and timeliness, complexities of monitoring adverse events in PCTs, whether PCTs should ever be stopped early due to futility, and any particular perspectives or expertise that may be useful on a DMC charged with monitoring PCTs.
- Which PCTs Should Have a DMC?
- Monitoring Protocol Adherence
- Data Issues With Monitoring PCTs
- Monitoring for Serious Adverse Events
- Futility Assessment
- Case Study: Planning for Monitoring PCTs
- Role of Stakeholder Perspectives
- Special Training and Resources for DMCs of Pragmatic Trials
- Additional Resources