As the pressure to reduce timelines rises across the industry, independent data monitoring committees (IDMCs) — which review ongoing clinical trial data to make recommendations regarding trial conduct based on risk-benefit — have been playing an increasingly larger role in sponsor submission activities. Part of the submission process is the time to produce the IDMC tables, listings, and figures (TLFs) and the time for the IDMC to review the TLFs in advance of an IDMC meeting where a recommendation is made regarding the trial in the context of a formal interim analysis (IA).
For all IDMC data review meetings, the time from the data snapshot to IDMC meeting should be minimized. The quantity of data to summarize for the IDMC directly impacts the time needed to prepare the TLFs as well as the time needed by the IDMC to review them. Timelines should consider the risk and the intention of the summaries.
To reduce timelines, sponsors should focus on IDMC meetings with a formal interim analysis where the recommendation may result in a submission. In this context, appropriate time should be taken during the initial programming and IA dry run to ensure that the IDMC programming is robust and accurate.
Initial IDMC data review meeting
Reducing timelines for meetings beyond the initial data review meeting, especially those with a formal interim efficacy or futility evaluation, is critical, and the more time invested at the beginning by a statistical data analysis center (SDAC) in producing quality TLFs, the more feasible this becomes. While a quick timeline may be achieved for the first IDMC meeting, failure to appropriately program for subsequent stages increases the risk that the more visible formal IA IDMC meeting will need to be pushed back. Conversely, appropriate time taken during the initial programming and IA dry run can help ensure the formal IA IDMC meeting occurs on time.
Subsequent IDMC data review meetings
For subsequent data review meetings without a formal IA, timelines can be reduced by focusing on drafts or dry runs. If the sponsor requires a review of the TLFs or programmatic cross-validation, this adds time between the data cut and IDMC meeting. It also increases the number of services that need to be provided and the time the sponsor spends preparing for the IDMC meeting. Removing a dry run generally decreases the entire IDMC meeting timeline by 15 business days. There is no need for additional dry runs after the initial meeting if there is no formal interim analysis. Without the formal interim analysis, there is no risk of stopping the study and preparing for submission. Therefore there is no need to substantially condense timelines on the essential tasks of supporting a subsequent IDMC meeting without a formal IA.
Maintaining typical timelines reduces the likelihood of needing to re-schedule IDMC meetings if there is a minor delay. IDMC members are often not immediately available for re-scheduling, and a minor delay in a data transfer may be compounded by an extended delay in IDMC meeting re-scheduling. This may require the sponsor to perform a new data cut and for the SDAC to rerun the DMC TLFs. Not cutting a potentially excess day is the cost if not needing to extend the timeline by weeks or even a month.
Subsequent IDMC data review meetings with a formal interim analysis
IDMC data review meetings with formal IAs are critical for submission and should be the focus of timeline reduction efforts. In some situations, the time available for these activities is days or weeks and not months, so efforts must be incredibly focused and scoped well in advance. The sponsor and SDAC should focus dry runs in advance of formal IAs on only the relevant efficacy outputs. The safety outputs have already been produced many times and don’t need to be reproduced. Focusing the dry run on only the efficacy TLFs generally reduces the typical IA IDMC meeting timeline by 7 business days.
Maximizing value of the IDMC to sponsors and participants
We’ve discussed where to look at reducing timelines based on the purpose of the IDMC meeting. A pre-requisite for these timeline reductions is that the IDMC TLFs are well-specified. The sponsor and SDAC should maintain approximately 30 TLFs for an IDMC data review meeting without a formal IA and 50 TLFs for an IDMC data review meeting with a formal IA. TLFs beyond those counts generally are not for the IDMC, but for the sponsor should the IDMC make a recommendation that results in proceeding toward a submission. TLFs beyond those created specifically for the IDMC are also generally created by the team supporting the CSR, so removing these from what’s produced for the IDMC results in efficiency for the sponsor and a focused report for the IDMC.
A poorly specified set of IDMC TLFs is often the result of IDMC TLFs where sponsors request modifications before each IDMC meeting. This reduces the IDMC’s familiarity with the TLFs, requires sponsor effort to review or implement the changes, and requires unexpected programming costs mid-study. Another source of poorly specified IDMC TLFs is utilization of end-of-study specifications and TLF templates that do not consider interim, unclean data. The resulting bolus of information from these approaches may require additional summary information to be provided to the IDMC and additional meetings to be scheduled before the IDMC is able to make a recommendation. This puts patient safety at risk in the meantime and may compromise sponsor timelines. For example, if the IDMC meeting is a formal IA where the potential outcome is to proceed to submission and the DMC can’t review all the information provided, then the DMC will require another meeting to process all the information they were given before making a recommendation.
A well-specified set of IDMC TLFs stays consistent from meeting to meeting unless changes are requested by the IDMC. They include IDMC-focused summaries, which concisely summarize data of interest to the IDMC in an often-graphical manner. This approach allows the IDMC to clearly track emerging data and doesn’t overburden the IDMC with extraneous information. The IDMC can quickly identify any concerns and make an informed recommendation about the study sooner than later, which minimizes the risk to patient safety.
Summaries for IDMCs should be specified at the outset to focus on key data relevant to the IDMC’s remit. Accurate and precise summaries are critical for the IDMC to make clear, actionable recommendations. The time from data cut to IDMC meeting should be minimized with a focus on subsequent data review meetings with a formal IA. This ensures any trends or concerns identified by the IDMC are actionable. The type and quantity of data to summarize for IDMC review directly impacts the time needed to prepare the summaries as well as the time needed by the IDMC for their review.
Focusing the data summaries ensures that the IDMC’s review is not obfuscated by irrelevant data, that the summaries are easily digestible for the IDMC throughout the life of the trial, and that the summaries can be produced with quality in a reasonable time. The above recommendations optimize the experience for the IDMC; result in reduced costs, timelines, and sponsor effort; and, ensure the IDMC will provide the greatest value to the sponsor and trial participants.
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:
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