Industry advises practical fixes for new FDA guidance on data monitoring committees

Stakeholder comments on new US Food and Drug Administration (FDA) draft guidance for data monitoring committees (DMCs) in acknowledgment of their expanding role include suggestions on early trials, blinding, conflicts of interest, and patient representation.

FDA released draft guidance in February for clinical trial sponsors and potentially third-party trials managers. (RELATED: FDA issues new guidance on data monitoring committees, Regulatory Focus 12 February 2024). Among other things, the guidance outlines:

When a DMC is needed
DMC responsibilities
Composition and charters of committees
Committee independence
Data confidentiality
Regulatory reporting requirements

Comments were open until April 13.

“Overall, the draft guidance provides valuable recommendations for sponsors of clinical trials in determining when a data monitoring committee (DMC) may be useful for trial monitoring and what procedures/practices should be considered to guide their operation,” South Korean biopharma Samsung Bioepis noted in its feedback to FDA.

Comments from the Pharmaceutical Research and Manufacturers of America (PhRMA) suggest that while DMCs have a unique role in clinical trial oversight and safety monitoring, there are caveats.

“PhRMA notes that DMCs may not necessarily evaluate efficacy in all circumstances, and we request that FDA explicitly state that this would be defined in the charter,” the trade organization wrote.

The Advanced Medical Technology Association (AdvaMed) noted that the guidance seems to be mainly for drug products and not medical devices.

“We recommend that the guidance be reviewed and revised to clearly include medical devices,” AdvaMed wrote. “For example, the guidance does not appear to contemplate that historical controls may be part of a trial design, that some trials are not conducted with control arms, and uses the term efficacy throughout without also referencing effectiveness.”

Expanding role for DMCs

The final document will replace the agency’s guidance Establishment and Operation of Clinical Trial Data Monitoring Committees from 2006. FDA said new guidance was needed because use of DMCs has expanded beyond their original focus on diseases with significant morbidity or mortality, toward use more broadly in conditions where specialized expertise is needed to evaluate emerging safety and efficacy signals, for example in rare diseases, vulnerable populations, and newer cancer therapies.

“DMCs are being increasingly used in trials of modest size and in multiregional trials due to the increased globalization of medicinal product development,” Samsung Bioepis wrote. “Furthermore, DMCs are increasingly used to implement certain adaptive clinical trial designs, as well as to oversee an entire clinical development program rather than a single clinical trial.”

FDA also noted in the draft guidance that DMCs are being increasingly used in early phase trials in serious diseases or conditions, with a variety of approaches at play. However, PhRMA observed in its comments that the draft guidance appears to be more focused on late phase, confirmatory trials and asked for more information on Phase 1-2 trials.

“As these trials often have different approaches to ongoing sponsor access to trial data than Phase 3 trials, we recommend FDA revise the guidance to address unique and practical considerations for the use of DMCs in these early stage trials,” PhRMA wrote.

For example, PhRMA wrote, since early trials are often exploratory, the sponsor’s study team must have access to data throughout the study.

“Accordingly, certain recommendations in the draft guidance relating to having an independent team (e.g., independent statistician) liaising with the sponsor and the DMC may not be necessary for early phase trials,” PhRMA wrote.

Challenging language on blinding

Some stakeholders flagged language around blinding and confidentiality of data. AdvaMed wrote that it disagrees with guidance language that a DMC or independent safety team should be blinded to efficacy/effectiveness data in the event of a possible adverse event that can only be detected by comparing event rates between the treatment and control arms.

“FDA fails to provide an explanation for this position in the draft guidance,” AdvaMed wrote. “There may be situations in which a DMC should review unblinded effectiveness data.”

Regarding this section, Regeneron Pharmaceuticals noted that DMCs reviewing safety data should not be precluded from reviewing efficacy data and wording clarifying this would align better with messaging found later in the document.

PhRMA noted that multiplicity adjustments for DMC unblinded reviews of summary safety and efficacy data are typically not needed.

“Accordingly, PhRMA recommends that FDA update the guidance to clarify that sponsors need not adjust the significance level of the final analysis to account for multiplicity specifically because the DMC is provided with access to accumulating, unblinded summary efficacy data in the context of their routine assessment of the emerging benefit-risk profile of the drug under study,” PhRMA wrote.

Samsung Bioepis asked for more information on how to maintain confidentiality through firewalls.

“In order to maintain the confidentiality regarding unblinded data and to preserve trial integrity, FDA has pointed out that maintaining appropriate firewalls between safety review entities and those directly involved in the conduct of the trial would be a helpful approach to be considered,” Samsung Bioepis suggested.

Minimizing conflicts of interest

Guidance document language about avoiding conflicts of interest among DMC members raised questions about practicality. While it is important to evaluate conflicts of interest, the FDA should allow more flexibility, PhRMA urged.

“Given both the proliferation of DMCs as well as the limited number of persons qualified to serve on DMCs, flexibility, including potential mitigating steps, may be needed in certain circumstances to adequately staff DMCs,” PhRMA wrote.

Similarly, Samsung Bioepis advised more flexibility on committee selection in light of the limited number of experts in some areas like rare diseases, as the draft recommends excluding people with strong views on the relative merits of an intervention being tested in a trial.

“We suggest that transparency and disclosure can play as important a role as a perception on conflict through prior involvement,” Samsung Bioepis wrote. “This will be particularly the case as efforts are made to ensure that patients and their representative communities are involved in the development of therapies for their conditions.”

The Cystic Fibrosis (CF) Foundation would like to see recommendations on inclusion of patients who live with a disease under study and/or their close relatives. FDA’s 2006 guidance on DMCs included representation of patients, the foundation noted.

“Given our own experience and the consensus across the broader clinical trial landscape, including the FDA itself and other leading institutions in the field, we strongly encourage the FDA to revise this draft guidance to include recommendations for incorporating the patient perspective into DMCs,” the CF Foundation wrote.

The CF Foundation would also like a guidance section on training considerations to address inclusion of patient representatives.

Industry advises practical fixes for new FDA guidance on data monitoring committees

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