Independent data monitoring committees review unblinded clinical trial data and issue recommendations to designated sponsor liaisons — but sometimes their recommendations are unexpected. Let’s take a closer look at how to preserve trial integrity after receiving an unanticipated IDMC recommendation.
Independent data monitoring committees (IDMC)
As an advisory group, an IDMC makes recommendations for a trial, while the final decision-making authority lies with the sponsor. Most recommendations made by IDMCs are anticipated, e.g., “continue the trial without modification.” However, when IDMCs make unanticipated recommendations such as “continue the trial with modification” or “stop the trial” due to efficacy or safety, sponsor liaisons are responsible for maintaining trial integrity as they consider whether to accept the IDMC’s recommendation.
Examples of unanticipated IDMC recommendations include:
IDMC recommends termination of the trial due to futility (outside of a formal futility analysis).
IDMC recommends discontinuation of a trial arm due to safety concerns.
IDMC recommends continuing the trial and meeting again in 3 months (instead of 6 months).
IDMC recommends halting enrollment of subjects in countries where a new standard of care has been recently approved.
IDMC recommends stopping enrollment in a subgroup with a poor risk-benefit ratio.
Here I provide a proactive framework for structured IDMC and sponsor liaison interactions, discuss risks to trial integrity while considering IDMC recommendations, outline materials commonly requested by sponsor liaisons, and conclude with several internal considerations for sponsors.
Framework for structured IDMC and sponsor liaison interactions
Sponsors should define a sponsor liaison who will be responsible for directly receiving all IDMC recommendations. This individual, who is not involved in the day-to-day operations and management of the trial, is empowered with clinical trial decision-making authority.
In the IDMC Charter, the name, title, and contact information for the sponsor liaison should be presented. This is often documented in an appendix with a note that the sponsor liaison may be updated without requiring resigning of the IDMC Charter. The IDMC Charter should also include the communication pathway, modality, and timing of IDMC recommendations. If the sponsor has defined committees that may be involved if an unanticipated recommendation is received, the potential involvement of those committees should be described. In addition, the following should be proactively addressed in the IDMC Charter:
Are sponsor committees involved by default or is it at the discretion of the sponsor liaison?
When is it expected for the sponsor liaison to request closed tables, listings, and figures (TLFs)?
Who is involved in discussions around whether to accept the IDMC’s recommendation?
How are discussions between the sponsor liaison and the IDMC documented?
How will discussions take place such that the discussions are invisible to the study team responsible for day-to-day trial operations?
The IDMC Charter should also include template recommendation forms for IDMC data review meetings and for formal interim analyses. The requested recommendation of an IDMC may be different for formal interim analyses. Specifically, the recommendation may consist of two parts: 1) the IDMC’s overall recommendation for the trial (expected), and 2) whether a specific statistical boundary was crossed (optional). Recommendation forms should not request the IDMC’s “rationale” or additional details that would not be suitable for distribution to an institutional review board (IRB). IDMCs will add a comment if they feel it is needed to clarify their recommendation.
After IDMC meetings, the written recommendation should be facilitated by the statistical data analysis center (SDAC) and delivered within one business day to the sponsor liaison. The sponsor liaison may request a meeting with the IDMC or the closed TLFs. If a meeting is requested, only authorized attendees should be informed, and minutes should be taken by the SDAC. The SDAC should exercise care in the review and storage of such minutes, so the appropriate audience is clear in the future. Often the meetings are scheduled quickly and the IDMC Chair represents the IDMC. If the closed TLFs are requested, the SDAC should confirm the list of closed TLFs to be provided, the recipient, and the transfer mechanism to ensure that only the intended recipient has auditable access. Any requests by the sponsor study team for the IDMC’s recommendation or closed materials should be answered without revealing the recommendation, without providing any unblinded materials, and without making any disclosures about interactions with the sponsor liaison.
Risks to trial integrity while considering IDMC recommendations
The primary purpose of the proactive framework for sponsor liaison and IDMC interactions is to safeguard the trial from the potential risks of information disclosure while the sponsor liaison is considering the IDMC’s recommendations. The table below details risks, related regulatory/advisory guidance, and the potential impact on the trial.
Sponsor individuals are simultaneously involved in receiving an unanticipated recommendation and managing the trial
“Sponsors may wish to develop internal procedures to limit the interim data released by an IDMC after a recommendation until a decision is made regarding acceptance or rejection of the recommendation, to facilitate maintaining confidentiality of the interim results should the trial continue.” (FDA Guidance)
Knowledge of a safety or conduct concern in aggregate may lead to changes in management of the trial or individual participants which could introduce bias.
If no change in protocol is eventually agreed to with the IDMC, this bias may carry into future management of patients which would not have been present if individuals managing the trial on a day-to-day basis were fire-walled from individuals making decisions about the trial.
Awareness of IDMC recommendation by individuals beyond those with direct decision-making capacity
“One concern is that unblinding of the sponsor increases the risk of further unblinding, e.g., of participants, potential participants, or investigators, thereby potentially compromising objective safety monitoring, equipoise, recruitment, administration of the intervention, or other aspects of the trial.” (FDA Guidance)
Dissemination of unblinded materials to individuals beyond those intended creates the reality or perception that bias could be introduced due to poor operational controls.
Recap sessions held after the closed session
“If verbal debriefings are held following meetings or issuance of IDMC recommendations, the minimal amount of information necessary to provide clarity should be provided.” (CTTI Guidance)
Operational individuals may be present. Sponsor may ask more questions than if questions were submitted in writing and the IDMC may be more willing to answer than if responses were submitted in writing. This risks additional disclosures beyond those that are minimally necessary to understand the recommendation.
Too many details on the recommendation form
“IDMC written recommendations to the trial sponsor should be conveyed with the minimal amount of information necessary to provide clarity.” (CTTI Guidance)
IDMC recommendations have a somewhat broad audience including IRBs and other committees responsible for the trial who could change their day-to-day management of the trial.
No pathway for the IDMC to discuss their recommendation with senior members of the sponsor
“Reaching reconciliation is also important, as otherwise the IDMC may see no choice but to contact the Ethics Committee or competent regulatory authority to stop the trial.” (EMA Q&A)
IDMC may reach out to outside stakeholders if they do not feel they have the pathway and audience needed to carefully discuss recommendations.
Materials commonly requested by sponsor liaisons
To evaluate an unanticipated IDMC recommendation, sponsor liaisons may request additional IDMC material via the SDAC. The three most requested materials following an unanticipated IDMC recommendation are the closed TLFs, closed IDMC meeting minutes, and a stand-alone rationale from the IDMC. The closed TLFs may include all or a subset of the closed TLFs reviewed by the IDMC as well as previous closed TLFs . A request for closed IDMC meeting minutes may include the most recent and/or previous closed IDMC meeting minutes. Finally, the sponsor liaison may request a stand-alone rationale from the IDMC that is independent of the recommendation form. The rationale for the IDMC’s recommendation, which may include information that is unblinding, is not included on the recommendation form beyond a carefully considered concise comment to preserve trial integrity given the audience of the recommendation form. In these cases, IDMCs often prefer to meet directly with the sponsor liaison.
Internal considerations for sponsors
When sponsors consider how they will address IDMC recommendations, the processes they develop should consider unanticipated IDMC recommendations. This ensures that the processes are sufficiently robust and appear the same to others in the organization regardless of the content of the IDMC’s recommendation. Sponsors should consider who is involved in discussions around whether to accept the IDMC’s recommendation. Sponsors may unblind a small, defined team of a biostatistician and a programmer to reproduce analyses and perform additional analyses. If a committee or individual is unblinded to evaluate an IDMC recommendation, what procedures does the sponsor have to reduce any future operational bias such as not making any future decisions for the trial? Sponsors should also consider their regulatory obligations if they receive an unanticipated recommendation.
Any IDMC meeting has the potential outcome of an unanticipated IDMC recommendation regardless of the scope of the IDMC or the expected TLFs being reviewed. A framework for structured sponsor liaison and IDMC interactions should be defined jointly by the sponsor, SDAC, and IDMC and prospectively laid out in the IDMC Charter. These steps ensure that trial integrity can be preserved. While this structure may only need to be minimally utilized if all IDMC recommendations are anticipated, it safeguards the interests of both the patients and sponsor should an unanticipated IDMC recommendation be received.
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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