DMC background
A DMC (often referred to as a data safety monitoring committee) is a group of individuals with relevant clinical, scientific, statistical, or other expertise. This group regularly reviews human subject data accumulated from clinical trials and provides recommendations to sponsors on whether to continue, modify, or discontinue clinical trials. In certain circumstances, the DMC may also provide recommendations on operational issues based on non-comparative safety and efficacy data.
Although sponsors are required to use DMC only for certain emergency studies, the use of DMC is increasing in many fields beyond the historical norm for diseases with significant morbidity or mortality. Masu. (21 CFR 50.24(a)(7)(iv) provides exceptions to the requirement to obtain informed consent for clinical trials in emergency situations. One of the conditions for such an exception is that (Establishment of an independent DMC.) FDA recognizes that DMCs are currently used to conduct moderate-sized clinical trials, conduct certain adaptive clinical trial designs, and oversee entire clinical development programs (rather than single clinical trials). It is pointed out that it has been done. In part, this draft guidance is an effort by FDA to update its recommendations for DMCs, given the significant changes that have occurred in the use of DMCs since FDA issued his guidance in 2006. This is considered to be an initiative.
Relationship between DMC and other monitoring groups
The draft guidance identifies institutional review boards, clinical trial steering committees, endpoint review/adjudication committees, clinical site monitors, organizations that review safety reports, and other groups that may be involved in clinical trials. It refers to certain relationships that DMC has. Adaptation Committee. DMCs are often the only group with access to unblinded safety and efficacy data accumulated in clinical trials. (FDA considers data to be unblinded when it reviews data by treatment group (for example, A vs. B) (even if the groups are identifiable). In general, other groups involved in a clinical trial may have access to such data to avoid biasing the results of the trial by inappropriately influencing the conduct of the trial or approach to analysis. It will not be. In contrast, DMCs can access this data for the following purposes:
- Monitor safety data
- Advise sponsors on the safety of human subject interventions
- Monitor interim efficacy results to determine whether they support benefit or no benefit.
- Helps ensure the scientific value and integrity of clinical trials
DMCs must maintain independence from their sponsors and therefore must not have any material financial ties to them. Additionally, DMCs should not be involved in the design or conduct of clinical trials. DMC independence is important for the following reasons:
- Ensuring that sponsor interests do not inappropriately influence the DMC
- Increase the objectivity of the DMC and limit the potential for bias.
- Preserves sponsors' ability to make changes to clinical trials without introducing bias.
- Keeping sponsors fully blinded helps prevent conflicts of interest for sponsors.
How you define independence is important. Too narrow a definition may prevent a knowledgeable researcher from becoming a member of her DMC.
Summary of draft guidance
Using DMC
In the draft guidance, FDA provides sponsors with considerations for deciding whether to use DMCs in a particular clinical trial. Such considerations include:
- Whether the use of DMC is practical in a particular clinical trial
- Degree of researcher, research facility, or other experience in the therapeutic area
- Participation of vulnerable people
However, FDA strongly recommends the use of DMCs when trial subjects are at risk of serious morbidity or mortality, even if any of these factors are not relevant. states.
Considerations for building and operating a DMC
Although the sponsor is responsible for establishing the DMC, the DMC must be independent of the sponsor and the conduct of the trial. The draft guidance describes how to appropriately achieve this independence, makes suggestions for the structure of a DMC, and outlines training considerations for DMC members.
FDA recommends that the DMC include:
- A person with specialized knowledge regarding the conduct of clinical trials
- Clinician with relevant clinical expertise
- biostatistician
- Members with experience working at DMC
- Members with FDA regulatory expertise
The agency also recommends considering the participation of individuals with expertise in informatics and technology. As clinical trials proliferate in the field of artificial intelligence (AI), the draft guidance does not address this, but in the spirit of the draft guidance, include members with computational or other relevant experience. Things become more and more wise.
Importantly, DMC members must be screened for both financial and intellectual conflicts of interest or bias. For example, DMC members may not have an ongoing financial relationship with a commercial sponsor of a clinical trial (or with a direct competitor of such sponsor). Additionally, individuals should not have intellectual conflicts of interest that could prevent them from evaluating clinical trial data objectively because they hold strong views about the relative merits of investigational drugs or interventions.
FDA also recommends establishing a DMC charter that describes the DMC's duties, responsibilities, and standard operating procedures. The DMC itself or the sponsor (with input from the DMC) can draw up the charter. The Charter must address:
- Specific information about configuring the DMC
- Meeting information, schedule, and format
- Planned analysis by DMC
- Data protection, if applicable
- How data confidentiality is maintained
Responding to DMC recommendations
The draft guidance states that if a DMC recommends a clinical trial to a sponsor based on an increased incidence of serious unexpected adverse events and a potential relationship with the investigational drug, the sponsor must investigate. It stipulates that If, as a result of the investigation, the sponsor concludes that there is a reasonable possibility that the event is related to the product, the sponsor must notify FDA of its findings. FDA also requires sponsors to notify FDA of all DMC recommendations related to investigational product safety, regardless of whether the adverse event underlying the recommendation meets the definition of “serious.” We recommend that you do so.
Although the DMC may make recommendations to the sponsor regarding whether to continue, modify, or terminate the trial, the final decision to terminate the clinical trial rests with the sponsor.
next step
You should evaluate the potential impact of the draft guidance and submit comments by April 15, 2024.