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Setting Expectations for Formal Interim Analyses with Independent Data Monitoring Committees

Independent data monitoring committees (IDMCs) review ongoing clinical trial data to make recommendations regarding trial conduct based on risk-benefit. Formal interim analyses (IAs) include pre-specified statistical boundaries for demonstrating efficacy and/or futility. These boundaries often do not consider other scenarios that may be present such as apparent futility in the absence of a formal boundary, discrepant trends in endpoints, limited other endpoint data, and external factors impacting study conduct.

Sponsors and IDMCs may have differing understandings of how an IDMC will operate:

    • Will an IDMC make recommendations based on all available information?
    • Will an IDMC make recommendations based only on the statistical boundaries?
    • Will an IDMC make recommendations outside of their remit in the IDMC Charter using their expertise?

These questions go beyond what is typically specified in the IDMC Charter. While all potential scenarios cannot be anticipated in advance, it is essential for sponsors and IDMCs to set expectations about how recommendations will be made. When sponsors and IDMCs do not set these expectations, the risk of the IDMC not knowing what the sponsor expects and the risk of the IDMC not being able to make an informed recommendation when expected increases. These risks translate to risk to participants in the trial and expanded sponsor timelines around IAs while expectations are aligned.

In this post, I’ll describe when sponsors should proactively set expectations with the IDMC, how to incorporate these expectations into the IDMC Charter, and when to refresh expectations with the IDMC before a formal IA.


The IDMC organizational meeting

An organizational meeting is held at the beginning of the study with the IDMC, sponsor, and statistical data analysis center (SDAC) such as Axio (a Cytel company). The purpose of the organizational meeting is to introduce the study to the IDMC and discuss how it will operate. During the organizational meeting, the IDMC should raise any concerns about the charge to the IDMC, the protocol, and the rationale for the study. The IDMC and sponsor should consider the questions posed above about how the IDMC will operate. The consensus reached between the IDMC and the sponsor must be documented in the IDMC Charter for future reference. At the organizational meeting, the IDMC should also raise concerns about the expected conduct (or lack thereof) of formal IAs. Discussion at a later point in time, beyond clarifying questions, would be informative to the sponsor.


The IDMC Charter

The IDMC Charter documents how the IDMC will conduct itself. The IDMC Charter should detail how the IDMC will make recommendations. IDMCs should strive to make recommendations as a consensus using the principles agreed to at the organizational meeting. Sponsors are responsible for appointing a single sponsor liaison who is responsible for receiving the IDMC’s recommendation. The sponsor liaison is an individual with decision-making authority for the trial, who is not involved in day-to-day decision-making for the trial. The IDMC Charter should detail when and how the IDMC’s recommendations are conveyed to this one individual. Sponsors should internally define a process for how they will handle an unexpected IDMC recommendation. Specifically, sponsors should consider having a designated committee that may be involved in evaluating an IDMC’s recommendation without involving the study team who delivers the trial.


Refreshing expectations before an interim analysis

It is essential to establish expectations at the start of the trial and ensure that expectations are clearly understood between the sponsor and the IDMC. The sponsor should provide the IDMC with the latest study documents via the SDAC well in advance of a formal IA. These documents include the current IDMC Charter, protocol, and Statistical Analysis Plan (SAP). This communication provides the IDMC with the opportunity to ask clarifying questions in advance so the sponsor can formally respond.

If an open session is held before the closed session of a formal IA IDMC meeting, sponsors should reiterate the expectations of the IDMC in a concise slide or two. This allows the IDMC to easily reference the expectations of them, how different recommendations are suggested to be captured on the recommendation form, and reduces the risk that the IDMC communicates the recommendation in a way that the sponsor was not expecting.

Finally, sponsors can engage the SDAC to write a non-editorial executive summary document that outlines: the charge to the IDMC, the critical values, the observed statistics, and the expected next steps. While sponsor teams are heavily involved in a particular study at the time of an interim analysis, most IDMC members are concurrently serving on multiple IDMCs in addition to other appointments. This step helps ensure that the IDMC can efficiently conduct the closed session and make a recommendation to the sponsor.


Final takeaways

At the time of formal IAs, sponsors are primarily concerned with obtaining a recommendation from the IDMC at the expected time. To help ensure the IDMC makes the most appropriate recommendation based on their remit at the time the recommendation is expected, sponsors should initiate proactive discussions with the IDMC during the organizational meeting, ensure that agreements are codified in the IDMC Charter, and refresh these expectations with their IDMC at the time of the interim analysis.


Interested in learning more about IDMCs? Click below to download our case study, which describes how Axio, a Cytel company, enabled a clinical-stage biotechnology company to accelerate the creation of DMC safety reports for four ongoing studies:


Read the Case Study

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