The US Food and Drug Administration (FDA) recently issued draft guidance with recommendations to help clinical trial sponsors determine when a data monitoring committee (DMC) would be beneficial for managing clinical trials and what procedures and practices they should consider when using a DMC, significantly revising past guidance from FDA. The comment period for feedback on the draft guidance is open until April 15.
The draft guidance substantially revises FDA’s 2006 guidance on Establishment and Operation of Clinical Trial Data Monitoring Committees and was prompted by changes in how DMCs are used in current clinical trials. Specifically, FDA notes there has been an increase in DMC use, a trend of longer and more detailed DMC charters, an expansion of DMC functions, and increased clinical trial globalization.
BACKGROUND
FDA defines a DMC as “a group of individuals with relevant expertise that reviews accumulating data on a regular basis from one or more clinical trials.” Generally, DMCs (also known as data and safety monitoring boards (DSMBs), data and safety monitoring committees (DSMCs), or independent data monitoring committees (IDMCs)) periodically review accumulating unblinded safety and efficacy clinical data, independent of the clinical trial team, and advise the trial sponsor on whether to continue, modify, or terminate a trial based on a benefit-risk assessment. DMCs are established by the study sponsor but are independent of the sponsor to ensure there is no bias in decision-making.
ASSESSING THE NEED FOR A DMC
Currently, FDA mandates the use of DMCs only when there is an exception from informed consent in emergency research settings. Since most trials do not require a DMC, sponsors should evaluate whether DMC review is practical and whether DMC review would have a meaningful positive impact on the study for a particular trial.
Examples of when a DMC may be of particular assistance include the following:
- A long-term trial, especially a multicenter study, trials using historical controls, or trials with an adaptive design and planned interim data analysis.
- For most short-term trials, use of a DMC to review interim data to assess continued exposure of subjects to the study product may be impractical and of little value. If, however, a DMC will be used for a short-term study, FDA recommends that mechanisms be established to permit timely DMC evaluation, such as dose escalation pauses or review by independent monitors.
- A study being conducted in a vulnerable population or where there is limited experience in a therapeutic area. While not specifically noted by the draft guidance, DMCs may also be helpful for studies involving newer or novel modes of treatment, such as gene therapies.
- A study involving a risk of serious morbidity or mortality (e.g., hospitalization, heart attack, stroke, death) to the trial subjects, including risks caused by the underlying disease or concomitant medications. This is especially the case when an analysis of safety data may be needed to determine whether an event is due to the investigational product or a subject’s background health condition and medications.
Whether a DMC is needed will depend on the circumstances of the individual trial. Sponsors should also consider whether the underlying purpose of the DMC would be better served by other study monitoring groups, including Institutional Review Boards, clinical trial steering committees, endpoint assessment/adjudication committees, clinical trial monitors, safety data reviewers, or adaptation committees.
Specifically with respect to adaption committees, FDA notes that, while DMCs can undertake adaptive decision-making when a trial has an adaptive design element, a DMC’s primary responsibility should be the evaluation of subject safety and trial integrity. Thus, if the underlying reason for convening a DMC is adaptive decision-making, an adaption committee may be more appropriate.
ESTABLISHING AND OPERATING A DMC
DMC Composition
Members of a DMC may include clinicians with expertise in the medical area under study, individuals with knowledge in current clinical trial conduct, and a biostatistician knowledgeable about statistical methods for clinical trials. Other types of expertise may be needed and should be assessed for trials on a case-specific basis.
FDA also states that it is “generally important to have some members with experience serving on DMCs and some members familiar with FDA regulatory requirements for clinical trials. Both types of experience are typically critical for the DMC chair.” For example, there may be a need for individuals with expertise in informatics and technology or a medical ethicist knowledgeable about the design, conduct, and interpretation of trials with unusually high risks to subject safety or with broad public health implications. DMCs are also frequently supported by an independent statistician or statistical group that provides statistical analyses and reports to the members for closed session consideration.
DMC members should have no conflicts of interest that could substantially affect a trial’s outcome, including no ongoing financial relationship with the trial’s sponsor or its direct competitors, or have strong views on the merits of the intervention(s) being evaluated in the clinical trial (i.e., intellectual conflict of interest or bias) that may prevent them from reviewing the data in a fully objective manner.
It is further critical that the DMC members understand their limited roles and responsibilities, and the questions being asked of them, for the particular trial. Accordingly, FDA encourages sponsors to consider training requirements for DMC members before the first DMC meeting and on an ongoing basis.
DMC Charter
All DMCs should operate under a written charter outlining the DMC’s roles and responsibilities. The charter should specify the possible recommendations that the DMC can make to the sponsor, the questions that the DMC is expected to address, operating procedures governing DMC deliberations to protect against concerns of bias over the course of the trial, the communication methods and processes between the DMC and the sponsor, methods to maintain data confidentiality, committee composition, and particulars of committee meetings (e.g., meeting schedule and formats, the types of data that will be available for review).
FDA may request a copy of the charter prior to the conduct of interim analyses or the initiation of a trial. Accordingly, it is critical that the charter clearly and thoroughly address a DMC’s specific responsibilities for the particular trial.
DMC Responsibilities
As independent reviewers of unblinded safety and efficacy data, DMCs are responsible for monitoring trial conduct and monitoring interim trial results for safety and, if required by the charter and study protocol, for effectiveness and trial futility and to make other types of prospectively specified adaptations to the trial design. Above all, the most recognized purpose of a DMC is to monitor the clinical trial for safety of the subjects.
A DMC should evaluate the study’s accumulating safety and make recommendations to the sponsor for study modifications on safety grounds. For example, if subjects given the investigational product are found to be at higher risk for mortality, disease progression, or loss of organ function than those given the control, the DMC may advise the sponsor to terminate the study or make other study changes for safety based on statistical considerations to avoid false conclusions of an adverse effect.
DMCs may also consider the impact of external information on a study, including results from studies of related products or other studies for the same product. In fact, when FDA has critical safety information about another trial for the same investigational product from the same sponsor that is relevant for the DMC’s review, the agency may request that the sponsor confirm that the DMC is aware of this data and is taking it under consideration.
To these ends, while programwide DMCs can be helpful, special consideration must be given to how trial results of related products will be shared when the members may not be the same across all trials in a program.
Notably, FDA states that a DMC’s role in safety monitoring should not be limited to only a review of safety data. Rather, when “determining whether the potential for safety risks is such that trial modification or early termination is warranted, a DMC should consider the potential for benefit in its deliberations.” As such, sponsors that are using a DMC will need to provide the committee with data sufficient for the members to make benefit-risk assessments.
DMC Recommendations and Records
FDA recommends that the DMC clearly document its recommendations and rationale to the sponsor in a manner that can be reviewed by the sponsor and then circulated to FDA and/or other interested parties. Written recommendations and oral communication to allow for questions and discussion between the DMC and sponsor are useful.
Moreover, when recommending study modifications, FDA states that these are “best accompanied by the minimum amount of data critical for the sponsor to make a reasonable decision about the recommendation, and the rationale for such recommendations should be as clear and precise as possible.” However, in these communications, care must be taken to maintain confidentiality of interim results to avoid jeopardizing the trial.
In addition, FDA recommends that the DMC keep meeting minutes for all of its meetings, issue a written report to the sponsor based on the meeting minutes, and maintain all meeting records to promote continued confidentiality of the interim data. FDA may request copies of records and reports relating to a clinical investigation and may also request access to electronic data sets used for the interim analysis. Therefore, FDA recommends sponsors make arrangements for archiving electronic data sets.
Minimization of Bias
It is particularly important to employ special provisions to minimize the potential for study bias and disclosure of unblinded interim results. Accordingly, sponsors should establish written procedures as part of the DMC charter to ensure that interim data is maintained as confidential. FDA also recommends that provisions for data confidentiality be made in written agreements between the sponsors and DMC members.
Some methods for maintaining interim data confidentiality include the establishment of firewalls between safety review entities and persons involved in the conduct of the trial, creation of closed and open reports to the DMC, and discussion of interim data only at closed DMC sessions. In small companies with limited personnel, it may be difficult to maintain confidentiality of the data from the DMC. Accordingly, precautions may be necessary to maintain walls around the company team responsible for the conduct of the trial.
Establishment of Evaluation Methods
Typically, a DMC will review analyses based on the prespecified statistical analysis plan (SAP). However, FDA notes that DMCs may also review additional exploratory analyses that are not specified in the SAP such as analyses regarding the likelihood of whether study success criteria will be met.
DMC REGULATORY IMPLICATIONS
Sponsors are required to investigate a DMC’s recommendation relating to safety events. Upon investigation, if the sponsor determines that there is a reasonable possibility that there is an increased rate of serious unanticipated adverse events associated with the study drug, the finding and support for it (e.g., the DMC report, any analyses, pertinent data) must be submitted to FDA as a serious unexpected suspected adverse reaction.
FDA considers an adverse event to be “unexpected” if it is not listed in the investigator brochure, is not listed at the specificity or severity that has been observed in the study, or is not consistent with the risk information described in the study’s investigational plan. FDA also recommends that sponsors inform the agency of all DMC recommendations related to the investigational product’s safety, whether or not the adverse event meets the definition of serious (e.g., recommendations to lower the study drug’s dose due to excess toxicity).
KEY TAKEAWAYS
Clinical trial sponsors will need to carefully consider this draft guidance when assessing the need for a DMC for their particular trial, including DMC establishment and operation. While for some trials a DMC provides an added layer of subject protection and a way to ensure that the trial is continually fit for its intended purpose, in other instances a DMC may not be appropriate or able to be usefully operationalized.
If sponsors determine that a DMC should be convened for their study, it is recommended that a DMC become familiar with the study protocol and other pertinent study information, including the DMC charter prior to participant enrollment.
As independence of the DMC from the sponsor is critical for enhancing objectivity and reducing the possibilities for bias, sponsors should evaluate their existing clinical trial protocols and operating procedures to ensure transparency when it comes to any DMC conflicting interests. FDA’s focus on patient safety and promoting trial integrity should also be considered in light of the agency’s reporting requirements that place compliance obligations on sponsors.
Finally, when establishing a DMC, it is critical that the DMC’s responsibilities are clearly set out in both the DMC charter and in agreements with DMC members so that there is no confusion later on regarding the role of the DMC in the particular study.
Interested stakeholders should comment on this draft guidance, with the comment period currently open until April 15, 2024.
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