A Data Monitoring Committee (DMC) is one out of several oversight groups monitoring the progress of a clinical trial; others include steering, adjudication or ethics committees. The talk sets out by describing situations requiring a DMC and then introduces some elementary aspects such as a DMC’s composition and organization (Herson, 2009; Ellenberg et al, 2019). Central to the organization of a DMC is the Charter as it defines the meeting format including open and closed sessions, the meeting intervals, the statistical analyses to be conducted and their reports. The information flow including the DMC’s interactions with the statistical analysis centre and the sponsor representative will be considered, in particular in contexts such as adaptive designs and programme level DMCs. Furthermore, we will discuss some statistical issues relevant to the monitoring of data such as the use of stopping boundaries (Mütze and Friede, 2020), the estimation of adverse event risks (Stegherr et al, 2021) and the integration of data across clinical trials (Friede et al, 2017).

References

Ellenberg SS, Fleming TR, Demets DL (2019) Data monitoring committees in clinical trials: a practical perspective. Wiley, 2^nd edition.

Friede T, Röver C, Wandel S, Neuenschwander B (2017) Meta-analysis of few small studies in orphan diseases. Research Synthesis Methods 8: 79–91.

Herson J (2009) Data and safety monitoring committees in clinical trials. Chapman & Hall / CRC, Boca Raton, FL.

Mütze T, Friede T (2020) Data monitoring committees for clinical trials evaluating treatments of COVID-19. Contemporary Clinical Trials 98: 106154.

Stegherr R, Schmoor C, Beyersmann J, Rufibach K, Jehl V, Brückner A, Eisele L, Künzel T, Kupas K, Langer F, Leverkus F, Loos A, Norenberg C, Voss F, Friede T (2021) Survival analysis for AdVerse events with VarYing follow-up times (SAVVY) - estimation of adverse event risks. Trials 22: 420.

Both the FDA and the EMA have guidance in place on independent Data Monitoring Committees (iDMCs) since 2006, much of which is still relevant and applicable today. More recent developments and potential controversies related to communication have triggered an additional EMA Q&A (1). Additionally, potential functions, roles and specific data needs of iDMCs in adaptive trials and more complex innovative design, such as platform trials, suggest rethinking some of the practices. Against this background, the presentation will address:

• The perspectives on importance and role of iDMC through all stages of drug development.
• Communication in the triangle of sponsor, iDMC and health authorities (including regulatory).
• The essential function of access to comprehensive data (safety and efficacy).
• Considerations of type 1 error, alpha spending and futility in case iDMC have regular access to efficacy data.

The points addressed will take into account relevant experience as iDMC member/chair when impactful advises were to be provided.

(1) https://www.ema.europa.eu/en/documents/scientific-guideline/questions-answers-data-monitoring-committees-issues_en.pdf

Well-designed graphics are a powerful way to communicate information to an array of different audiences. In randomised controlled trials (RCT) where there is an abundance of complex data on harm they can be a highly effective means to summarise harm profiles and identify potential adverse reactions offering an alternative perspective to the traditional frequency tables. Advances in computer software have improved trialists’ capability to produce visualisations; however, little guidance exists on what and how to visually display complex harm data. Therefore with an abundance of visualisation options available and the increasing ease with which they can be implemented we have previously identified researchers’ recommendations for visualising harm outcomes with an aim to improve reporting practice in journal articles (1). In this presentation we will extend these ideas to the Data Monitoring Committee (DMC) report. We will present a variety of visualisations dependent on outcome type e.g., binary, count, time-to-event or continuous and the scenario e.g., summarising multiple emerging events or one event of interest. Contrasting these with typical presentation formats (e.g. tables and listings) in DMC reports. We present a decision tree to aid trialists in their choice of visualisations alongside each of the endorsed visualisations, with example interpretation and potential limitations.

1. Phillips R, Cro S, Wheeler G, Bond S, Morris TP, Creanor S, et al. Visualising harms in publications of randomised controlled trials: consensus and recommendations. BMJ. 2022;377:e068983.

To make informed recommendations to the sponsor, Data Monitoring Committees (DMCs) periodically receive sensitive and potentially unblinded data, during a period of study conduct when the sponsor study team is still blinded. The involvement of a Data Analysis Center (DAC), independent from the Sponsor study team, is the optimal way to facilitate the preparation and presentation of the DMC reports. This team can be unblinded and can facilitate ad hoc DMC requests without compromising the integrity of the clinical trial. In this session, we will present the role of the DAC, from the receipt of trial data to the DMC’s recommendations during the closed session. Different programming operational models will be described, associated with their respective advantages and challenges for the sponsor, the DMC, and the DAC, and with a particular focus on the capability for the DAC to respond to ad hoc DMC requests without involving the study team.

The sponsor of a study establishes the DMC and sets up the structure by which the DMC and the independent statistical analysis center operate, described in the DMC charter. This presentation will highlight best practices for the sponsor to enable the DMC and the independent statistical analysis center to function efficiently, with an emphasis on ensuring study integrity. The presentation will also suggest areas for improvement in the DMC process from the sponsor perspective. Considerations for forming the DMC will be discussed, and the importance of prespecifying operating procedures and communication channels will be emphasized.