Data monitoring committees (DMCs) review ongoing clinical trial data to make recommendations regarding trial conduct based on risk-benefit. DMCs are an essential component to ensuring the integrity and safety of clinical trials. New draft guidance published by the U.S. FDA on the use of DMCs in clinical trials provides six major updates to the FDA’s expectations regarding DMC structure and practice. The draft is open to public comment until April 15, 2024.
We highlight the updates provided in this draft guidance and discuss the impact on sponsors.
The role of the DMC in clinical trials
The DMC is an essential part of many clinical trials — particularly (but not exclusively) for randomized, blinded clinical trials. In such studies, neither the patients, nor the treating physicians, nor the sponsor know the results of the study until its conclusion. There are good reasons to have this blinding in place. However, any important emerging signals would also not be known until the study’s conclusion. Having an independent DMC review these potential emerging signals puts a process in place to allow for changes in the conduct of the ongoing clinical trial while still maintaining its scientific integrity. The DMC reviews emerging safety and efficacy data to assess risk-benefit and recommend changes, as needed, to protect the patients — patients in the study, patients yet to be enrolled, and the larger patient population.
FDA draft guidance on the use of DMCs in clinical trials: What’s new
The original FDA draft guidance for DMCs, finalized in March 2006, was sorely needed for the pharmaceutical and biotechnology industry, which was not experienced in DMC best practices. For example, it was not uncommon at that time for sponsors to attempt to have their own employees serve as DMC members, or to sit in as non-voting members (but still with access to unblinded results). Establishing written guidance about what a DMC charter should include, the DMC’s responsibilities, and the need for independence of the DMC was an important step forward.
However, many DMCs at that time were focused on large, multi-center, Phase 3 cardiovascular studies. In the past 20 years, there has been an explosion of DMC use in different disease areas and different phases of clinical trials. For that reason and many others, it is another appreciable step forward to have this updated draft guidance.
The updated draft guidance1 notes six changes to DMC structure and practice:
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- The increased use of DMCs in trials2 of modest size as reflected in the clinical trials data bank housed at ClinicalTrials.gov.
- A trend for DMC charters to become longer and more detailed.
- An increased use of DMCs to implement certain adaptive clinical trial designs.
- An increased use of some DMCs to oversee an entire clinical development program rather than a single clinical trial.
- The potential for expansion of functions of a DMC; for example, for review of aggregate data for safety reporting for trials under an investigational new drug application (IND).
- An increased globalization of medical product development and use of multiregional trials with DMCs.
- The increased use of DMCs in trials2 of modest size as reflected in the clinical trials data bank housed at ClinicalTrials.gov.
What are the major implications of the updates to the draft guidance on DMCs?
Let us discuss each change and its implication for sponsors:
Increased use of DMCs in modestly sized trials
We now see DMCs frequently utilized in late Phase 2 studies, and even early Phase 2 and Phase 1 studies. The purpose of the DMC can be quite different. For example, a DMC serving on a Phase 1 study may see the same results as the study team (no randomized treatment) but can serve as an independent body when helping to decide if results indicate it is safe to proceed to a next cohort. In Phase 2, the DMC may be more focused on helping to assess the safety of different doses.
Larger and more detailed DMC charters
A negative trend is prescriptive DMC charters. DMC charters should describe the general philosophy and communication plan — but defer to the expertise of the DMC as it is virtually impossible to proactively imagine all of the ways that the data and overall context of the study could evolve over the years of the study. DMCs should be allowed wide latitude to receive and analyze the data as needed to protect patient safety and trial integrity.
Increased use of DMCs to implement adaptive clinical trial designs
More DMCs are being exposed to adaptive clinical trial designs — particularly those that are different from the traditional group sequential designs. The DMC will need strong support from the Statistical Data Analysis Center (SDAC) facilitating the DMC’s review to help program and explain the implications of these designs. In some cases, the review of results from these adaptive clinical trial designs might be handled by a different independent group (the draft guidance refers to an Adaptation Committee) — although then the full context of risk-benefit analysis would be lost, and it introduces logistical challenges of interactions between multiple monitoring groups.
Increased use of DMCs to oversee an entire clinical development program rather than a single clinical trial
The past few decades have seen a proliferation of DMCs that review multiple studies — the “program-wide DMC.” This could be the full DMC overseeing multiple studies with the same investigational product but different disease areas. Or perhaps just a few DMC members overlap between studies (e.g., the DMC statistician and DMC chair) with the other clinicians chosen for their specialty for each individual study. The pros are many: more efficient review and better ability to detect important but relatively rare safety signals. There are cons as well: more time needed by everyone, including by the sites and sponsor for data preparation of multiple studies reviewed at the same time, by the SDAC for creations of multiple outputs, and by the DMC for review of multiple studies. It is important that the SDAC carefully lead the DMC through review in closed session to avoid possible confusion between the different studies.
Potential expansion of DMC functions
Many regulatory agencies are interested in being updated on safety signals, but not being bombarded with hundreds of individual SAEs or SUSARs. They want to know about signals where events are occurring at higher rates on an investigational product compared to control arms or historical rates. That is easy for sponsors of completed studies, but a challenge when the wish is to also include active studies into the calculation. A DMC could play a role in triggering some safety signals for further review, such as by a firewalled Safety Assessment Committee within a sponsor. The DMC would not necessarily recommend any change in study conduct but could identify when the thresholds for further investigation and possibly notification of regulatory agencies are met.
Increased globalization of medical product development and use of multiregional trials with DMCs
Most studies are multinational. This has implications for DMC membership and analysis. It is only logical that a study run primarily in Asia Pacific, for example, should have representation from that region on the DMC to have someone who understands the standard of care within the region and other local considerations. It may be reasonable to have some key outputs split by region or country to look for consistency of results (while also being highly aware of the dangers of subgroup analyses). Some countries will require a minimum enrollment from their country, and therefore the DMC may extend their review while subjects from only one country remain to be enrolled and treated and followed. There may even be different endpoints or analyses required by different regulatory agencies, adding complexity to DMC decision making. In such instances, the endpoints and/or analyses on which to focus may differ by groups.
Final takeaways
DMCs are a critical component of protecting patient safety in clinical trials. Although still a draft currently, much thought has been put into this latest FDA document. It is important that sponsors, DMCs, and SDACs understand the document and consider it as laying out the best practices for DMCs.
Interested in learning more? David Kerr, Director, DMC Services, will be hosting open Office Hours on Tuesday, April 9, from 2–3 pm EDT. He will be joined by Kent Koprowicz, Vice President, DMC, and Bill Coar, Senior Director, Biostatistics. Click to register:
About David Kerr
David Kerr is Director, DMC Services, at Axio, a Cytel Company. He has worked at Axio for 28 years and specifically for DMC activities on over 250 studies and attended over 1,000 DMC meetings in disease areas such as oncology, cardiology, infectious disease, respiratory disease, and rheumatology. His goal is to make sure the DMC has the best information available to help them make educated recommendations for the success of the trial and the protection of the study patients.
Notes
1. U.S. Food and Drug Administration. (2024). Use of Data Monitoring Committees in Clinical Trials.
2. Califf, R., Zarin, D., Kramer, J., Sherman, R., Aberle, L., and Tasneem, A. (2012). Characteristics of clinical trials registered in ClinicalTrials.gov, 2007–2010. JAMA, 307(17).
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