Data Monitoring Committees (DMCs) review unblinded clinical trial data and issue recommendations on trial conduct to designated sponsor liaisons empowered with decision-making authority. As an advisory group, a DMC is empaneled by a clinical trial sponsor to safeguard trial participants and ensure the scientific integrity of a trial.

To best support the DMC, sponsors should provide access to benefit summary data so the DMC can make informed recommendations based on risk-benefit at each DMC data review meeting. However, DMCs are often only provided with benefit summaries upon request. This informs the sponsor that the DMC has a concern about risk/benefit, which in the presence of no benefit data, implies that there is a safety concern.

Here, we discuss relevant regulatory guidance regarding risk-benefit assessments conducted by DMCs and the importance of providing appropriate benefit summaries by default to best protect trial integrity and the safety of trial participants.

Regulatory guidance on DMCs in clinical trials

The FDA, EMA, and CTTI all give some guidance on DMCs assessing risk-benefit. These organizations all suggest that data that describes patient benefit should be considered when evaluating an intervention.

FDA: “Use of Data Monitoring Committees DMCs in Clinical Trials”

This draft guidance is intended to help clinical trial sponsors determine when a data monitoring committee (DMC) would be useful for trial monitoring and what procedures and practices should be considered to guide their operation.1 Regarding risk-benefit assessments, the guidance states:

• “In order to adequately assess the benefits and risks of an intervention, the DMC should evaluate safety data within the context of the intervention’s efficacy, such that the DMC should have access to safety results as well as comparative efficacy results.”

Regarding oncology studies, the guidance adds:

• “DMCs can provide the specialized expertise … for oncologic therapies with highly specific targets and potential serious risks (e.g., biological products for genetic targets, immunotherapies).”

FDA: “The Establishment and Operation of Clinical Trial Data Monitoring Committees”

This final FDA guidance is also intended to help clinical trial sponsors determine when a DMC may be useful for study monitoring as well as how these committees should operate.2

At formal interim analyses, the guidance notes, risk-benefit should be considered along with formal statistical boundaries:

• “The data on effectiveness may be very strong, with a stopping boundary having been crossed, but emerging safety concerns may make the benefit-to-risk assessment non-definitive at that interim review.”

• “If the interim data suggest that the new product is of no benefit—that is, there is no trend indicating superiority of the new product—or that accrual rates are too low or noncompliance too great to provide adequate power for identifying the specified benefit, a DMC may consider whether continuation of the study is futile and may recommend early termination on this basis.”

European Medicines Agency: “Guideline on Data Monitoring Committees”

The EMA’s guideline highlights the key issues involved when sponsors include DMCs as part of their trial management.3 Regarding safety monitoring, the guidance notes:

• “In most cases, safety monitoring will be the major task for a DMC. Even if the safety parameters monitored are not directly related to efficacy, a DMC might need access to unblinded efficacy information to perform a risk/benefit assessment in order to weigh possible safety disadvantages against a possible gain in efficacy.”

CTTI: “Recommendations: Data Monitoring Committees”

The Clinical Trials Transformation Initiative (CTTI),4 the public-private partnership co-founded by Duke University and the FDA, offers the following recommendation:

• “DMC members should be independent of the trial sponsor and should be provided with adequate resources and flexibility to perform their role of assessing benefit-risk (e.g., performing ad hoc analyses as needed, having full access to accumulating unmasked study data).”

Providing appropriate benefit summaries

Common benefit summaries include data around how the patient feels, functions, or survives and does not necessarily imply formal inferential efficacy summaries. In oncology, for example, benefit data are commonly overall tumor response data or overall survival data without inferential summaries. In fact, overall survival data in oncology studies plays a key role in risk-benefit assessment if an investigational product is not performing as expected.

Sponsors can best support DMCs with access to appropriate benefit summaries before requests for such summaries become informative, discussing with the DMC in advance what data would be especially useful for them to have beyond the standard safety profile.

Final takeaways

DMCs should be provided with benefit summaries from the outset. Providing the benefit summaries by default ensures that the DMC’s recommendations are timely since the DMC doesn’t have to wait for the additional summaries to be provided, which protects participant safety. Providing the benefit summaries by default also ensures that sponsors are not informed that there is a safety concern when the DMC asks for additional summaries, which protects trial integrity.

Interested in learning more?

Join Becky Gatesman and Emily Woolley for their upcoming webinar, “Patient-Centric Risk-Benefit Assessments by DMCs” on Wednesday, December 3 at 10 am ET:

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