FDA recently issued a draft guidance on the use of data monitoring committees (DMCs) in clinical trials entitled “Use of Data Monitoring Committees in Clinical Trials.” When finalized, this guidance will replace the 2006 final guidance on the same topic entitled “Establishment and Operation of Clinical Trial Data Monitoring Committees.”

A DMC[1] is a group of experts that reviews accumulating data from one or more ongoing clinical trials in order to monitor the continuing safety of trial subjects and those yet to be recruited to the trial. DMCs have a unique role in clinical trial oversight because they are often the only group with access to accumulating unblinded safety and efficacy data while the trial is being conducted.

Evolving landscape

Responding to the expanded use of DMCs, FDA has reopened the comments on its DMC guidance to offer stakeholders the chance to help shape its advice for how DMCs should operate. The 2024 version of the guidance differs from the 2006 guidance in that it responds to perceived “significant changes in DMC structure and practice,” including:

• The increased use of DMCs in trials of modest size as reflected in the ClinicalTrials.gov clinical trials data bank

• 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 (e.g., trials involving the same investigational product in different populations) 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

Moreover, FDA recognizes that several different groups and individuals may assume or share responsibility for various aspects of clinical trial monitoring and oversight and stresses the importance of clearly defining the roles of all trial stakeholders (such as clinical trial steering committees, endpoint assessment/adjudication committees, and site/clinical monitoring teams).

When a DMC is advisable

FDA “strongly recommends” establishing a DMC if trial subjects are at risk of serious morbidity or mortality (e.g., hospitalization, heart attack, stroke, death); or when investigational products may cause serious unexpected adverse events. The agency understands, however, that DMCs are rarely required by FDA’s regulations and, moreover, may not always be practical (e.g., trials with fast enrollment and a short follow-up period). With that understanding, FDA advises sponsors when determining whether to establish a DMC to consider (a) the risk to trial participants and (b) whether a DMC is practical.

For example, FDA recommends that sponsors consider using a DMC when:

• There is prior information suggesting the possibility of serious toxicity with the study treatment.

• The study is large, of long duration, or multi-center.

• Subjects are from a vulnerable population.

• There is limited experience in the therapeutic area.

Strengthened recommendations regarding conflicts of interest

FDA has maintained much of its advice in the 2006 guidance concerning potential conflicts of interest. The draft guidance continues to suggest that a conflict of interest may be present where a potential DMC member has a financial interest that could be substantially affected by the trial results; the potential member is involved in conducting the study; or where the potential member is known to have strong views on the relative merits of the study intervention (referred to as an “intellectual conflict of interest”).

Notably, FDA has strengthened the language in the draft guidance regarding financial conflicts of interests for DMC members. In the 2006 guidance, the agency stated that:

[We] recommend that these members generally have no ongoing financial relationship with a trial’s commercial sponsor ….[2]

By contrast, the new draft guidance takes a more stringent and definitive stance with respect to financial conflicts of interest:

Aside from being compensated for their duties on the committee, DMC members should have no ongoing financial relationship with a trial’s commercial sponsor (or its direct competitors) ….[3]

Another noteworthy addition to the draft guidance is FDA’s declaration that a financial conflict of interest is present where an individual has an ongoing financial relationship with the sponsor’s “direct competitors,” which FDA defines as the sponsor of a study for a product that is or would be competitive with that being evaluated. This update may have broad implications for studies in a competitive or narrow disease landscape.

Study sponsors that establish DMCs should take note of these changes to FDA’s position on conflicts of interest and should carefully document their assessment of potential conflicts when selecting DMC members.

Other recommendations

Similar to the 2006 guidance, the 2024 draft guidance contains recommendations regarding:

• DMC committee composition. The draft guidance describes how “a well-constructed DMC should be equipped to identify unexpected issues and mitigate problems that could otherwise cause risk to subjects or could adversely affect the quality of the data and integrity of the trial.” To that end, it provides recommendations on DMC committee membership, conflicts of interest issues, and training guidelines.
• Components of a written charter. FDA spells out how all DMCs should operate under a written charter that clearly states the purpose of the DMC, the specific questions it is expected to address, and the possible recommendations it can make to the sponsor during the trial. The DMC charter and documented concurrence with the charter by all DMC members should be in place in advance of performing any interim analyses and ideally before the initiation of the trial and any subject enrollment. The agency may request a copy of the charter.
• DMC responsibilities. The draft guidance outlines how the DMC should consider various matters related to trial conduct, including clinical trial monitoring, interim data analysis, and monitoring for safety, efficacy, futility, and trial adaptations.
• Interim data analyses. Recognizing the risk of study bias, FDA emphasizes the importance of confidentiality of any interim data or interim data analyses and, specifically, that unblinded interim data and the results of comparative interim analyses should generally not be accessible by anyone other than DMC members or the statisticians performing these analyses.
• Consideration of external data. In instances where a DMC is asked to consider the impact of external information on the trial being monitored, FDA cautions that this may introduce study bias and advises that sponsor to exercise care when presenting this information to the DMC. One example of relevant external data would be the results of a related trial (e.g., a trial of a pharmacologically related drug or comparable device).
• Recommendations and documentation. FDA advises that a DMC should express its recommendations clearly to the sponsor and keep minutes of all meetings but use separate minutes for open and closed sessions. FDA notes that it has the right to request copies of these records when the trial is completed. In addition, FDA clarified for sponsors that the motivation for the DMC’s recommendation should be analyzed to determine whether it may trigger a reporting requirement (e.g., trial modification could be based on the DMC’s finding that there was an increased rate of serious and unexpected AEs in the investigational product arm).

*           *           *

FDA is seeking comments on the draft guidance through April 15, 2024. If you are interested in submitting a comment or have questions on data monitoring committees or clinical trials more generally, please contact the Hogan Lovells attorney with whom you regularly work or any of the authors of this alert.

Authored by Robert Church, Heidi Gertner, Blake Wilson, Stephanie Agu, and Eva Schifini