Independent data monitoring committees review unblinded clinical trial data and issue recommendations to designated sponsor liaisons. Characteristics of cell and gene therapy trials often require slightly different approaches to IDMC conduct in comparison to typical pivotal trials. Here I will discuss the conduct of IDMCs for cell and gene therapy trials. I will cover the differences that are unique to these therapeutic areas and how those differences impact how the IDMC operates. I will note potential pitfalls in IDMC conduct and introduce mitigation strategies. Specific areas of exploration will include IDMC member and SDAC selection, IDMC report preparation, IDMC reporting specifications, and IDMC meeting conduct.
Trial characteristics that impact IDMC conduct
The typical IDMC use case is for large randomized clinical trials with more than 100 patients. These are often later-stage trials — primarily Phase III — with some Phase II and some Phase IV trials. These trials typically have a comparator arm. The trials may be open label, specifically, if it is not possible to blind administration of the arms due to differences in treatment administration routes or frequency of treatment. Some trials in this space are placebo controlled. The time horizon for IDMC monitoring, patient enrollment, and treatment period in this space is years.
In the cell and gene therapy space, we see differences from the typical IDMC use case. These can be trials with lower enrollment targets, such as fewer than 100 or sometimes even fewer than 20 patients in the trial. They’re often earlier-stage trials or use adaptive designs to incorporate multiple phases. The trial may or may not be randomized. There may not be a reasonable comparator arm. The time horizon for these trials is often measured differently: the enrollment period is often measured in days or weeks, and the treatment period may be measured in a single day, days, or weeks.
Broadly, IDMCs are responsible for assessing risk/benefit of a smaller group of patients, or even individual patients. Turnaround times are rapid. There is also often less early-phase data available for context than an IDMC supporting a Phase III trial might have access to.
Trial conduct issues that can impact the IDMC
There are four areas of trial conduct issues that may impact the IDMC.
The first potential conduct issue is getting patients dosed with the appropriate dose level. Patients may receive a dose that is not sufficient to achieve the expected therapeutic result. Dosing issues may also result in excess dosing creating unexpected toxicity. These two dose situations may require adjustment of the overall trial dosing as set forth in the protocol after an early look at the results. From the perspective of the IDMC, these situations lead to patients having varying doses, which makes it difficult for the IDMC to interpret safety and efficacy data. There may be patients with insufficient dosing, patients with excess dosing, and patients with just right dosing later in the trial. Changes to the dosing, and therefore of the protocol, means that the sponsor is conducting analyses and having regulatory interactions around the dosing. The IDMC needs to understand the nature of these interactions at a high level and the data observed to date so that they understand how the trial is being conducted and why.
Other issues are manufacturing and product issues around having the product available. Patients may never be dosed because there was a manufacturing issue with a specific batch or a dose that was intended for a specific patient. Patients may never be dosed due to temperature excursions in transit or a lost shipment. From the perspective of the IDMC, these situations lead to patients with varying treatment disposition. Some patients are treated, and some aren’t. This can make interpretation difficult at the trial level.
Another consideration is the impact of individual- and site-level data. In a smaller trial, each patient’s data has a relatively greater marginal impact on the interpretation of the trial. With a novel treatment therapy, investigators who are familiar with the product are needed so that they can administer the product and protect patient safety. This may result in a small number of sites, or a single site being used. From the perspective of the IDMC, this can lead to difficulty in terms of interpreting data if data for a patient or a site are missing or incomplete.
The final consideration I’ll discuss are seamless designs and adaptations. These trial designs are often Phase II/III with data reviews for pre-specified adaptations scheduled at intervals. Due to the way these trials are designed, they require an IDMC to review results at the pre-specified intervals and make recommendations to protect the integrity of the trial. From the perspective of the IDMC, seamless designs require many considerations.
The SDAC needs to consider how IDMC reporting will change over time. There are the possibilities of dropping treatment arms, adding treatment arms, and expanding the sample size. How would those changes impact the IDMC TLFs?
The IDMC must clearly understand their role in the adaptation decisions.
Will IDMC recommendations be based only on the adaptation rules?
Will the IDMC also consider the data from the trial as a whole?
Will the IDMC consider the adaptation rules in conjunction with both the data from the trial as a whole and their expertise as IDMC members?
The IDMC also considers trial conduct. In these trials, that often surrounds what informed consent means for a patient as the trial changes. What known risk/benefit are prospective patients consenting to given the trial’s progress and results thus far?
Trial changes mean that acceptable risk/benefit change over time. The IDMC should consider what constitutes acceptable risk/benefit for the trial to continue at each data review meeting and at each pre specified adaptation point.
Potential pitfalls and mitigation strategies
With differing trial characteristics and trial conduct, there are several potential pitfalls that must be considered and mitigated. The first potential pitfall is IDMC member and SDAC selection. IDMC meetings may be scheduled with limited advance notice. Potential IDMC members should be made aware of this likelihood before contracting them to serve as IDMC members. If potential IDMC members do not have the ability to attend IDMC meetings with limited advance notice, they’re not good candidates for serving on an IDMC in this space. Similarly, the SDAC must be able accommodate quick requests to schedule an IDMC meeting.
When making recommendations, the IDMC needs to be comfortable making recommendations based on a limited number of patients. Not all potential IDMC members are comfortable doing this, so it’s important to recruit members who are.
Trials under review may be single-arm trials. This can pose difficulties in terms of interpretation without a comparator arm. Provide the IDMC with the draft protocol before they commit to serving as an IDMC member so they can understand exactly which data will be collected and that there is no comparator arm. Trials may also be at an earlier phase, where the rigidity of IDMC conduct around best practices and standards may not be applicable. Some potential IDMC members are less flexible about these realities than others.
For IDMC reporting specifications, expect a quick turnaround from data snapshot to IDMC meeting. For this to be feasible, the summaries prepared for the IDMC must be incredibly focused and need to address potential safety stopping rules. One approach is to plan for patient profiles from the outset so individual patients can be reviewed quickly. The TLFs should also address potential questions around enrollment and pauses or restarts. For IDMC TLF preparation, limited data are available for programming. After initial programming, a subset of the TLFs may be produced for the first meeting. Also expect reduced timelines around dry runs. This requires agreement between the sponsor and the SDAC about items that are critical to fix in the DMC TLFs versus items that are nice to fix. The focus must be on critical to fix items.
There is a quick turnaround from data snapshot to IDMC meeting. This requires an SDAC who can accommodate the quick turnaround with little advance notice. A typical IDMC report size cannot feasibly be produced on the timelines that are necessary to support these trials. In addition, a typical set of IDMC TLFs is often not interpretable with limited patients and limited data. The TLF for the IDMC should be critically considered. Summary tables should be limited to disposition and high-level safety data. The TLF may also require supplementation with narratives from the sponsor to have a comprehensive picture of the experience of individual subjects.
For IDMC meeting conduct, review of single-arm trials will likely require more than one hour in the open session and less than one hour in the closed session. Most of the discussion is going to occur in the open session where the IDMC can gain insights from the sponsor. Sponsors should be prepared to address questions from the IDMC about the data and about data for similar trials in the open session. Regardless of how much data is discussed in the open session, a closed session should always be held to allow the IDMC to fully consider their recommendation and maintain their independence.
From the perspective of the DMC members, serving on an IDMC in the cell and gene therapy space requires the members to have flexibility, attend meetings with little advance notice, and make recommendations on a small number or individual patients. SDACs supporting IDMCs in this space must be nimble to support quick scheduling and programming and production of IDMC TLFs with reduced turnaround times. Sponsors supporting IDMCs in this space should focus their requests of the IDMC, be willing to provide written narratives as needed, and keep the IDMC informed of key trial developments as the trial progresses.
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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