Eighteen years after issuing the first guidance for clinical trial sponsors entitled “Establishment and Operation of Clinical Trial Data Monitoring Committees” issued on March 28, 2006, the Food and Drug Administration revisits the topic of the DMC (also known as a DSMB, a DSMC, or an IDMC) acknowledging that much has changed in the clinical research landscape and that a new vision and a new governance is needed in order to cover the additional areas where DMCs are needed – and used – today. A quick dive into the guidance content.
On 16 February 2024, the FDA posted a draft guidance for industry entitled “Use of Data Monitoring Committees in Clinical Trials,” for public feedback until April 15th, 2024. The rationale for updating the Guidance and instructions for providing comments are detailed in an FDA notice dated 02/13/2024 which can be found on https://www.federalregister.gov/documents/2024/02/13/2024-02849/use-of-data-monitoring-committees-in-clinical-trials-draft-guidance-for-industry-availability-agency
Rationale for the new guidance
In the notice, the FDA acknowledges that, while the use of DMCs was initially reserved to large studies in disease areas associated with significant morbidity or mortality, in recent years the use of DMCs was extended to smaller studies and to many disease areas not involving serious morbidity or mortality. The growth of Data Monitoring Committees use however was not governed by specific regulations resulting in the development of a variety of approaches to DMC operations. Changes to the guidance aim to fill this gap by reflecting changes in DMC structure and practice.
As one of the main reasons for the current update, the FDA lists the following significant changes in DMC structure and practice since the 2006 guidance was issued:
- The increased use of Data Monitoring Committees in trials of modest size as reflected in the clinical trials data bank housed at ClinicalTrials.gov
- 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 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
Who is concerned?
According to the proposed text: “This guidance pertains primarily to the sponsor's responsibility for clinical trial management and decision making but may also be relevant to any individual or group to whom the sponsor has delegated applicable trial management responsibilities.” Therefore, both sponsors and CROs have an interest in carefully reviewing the draft text and incorporating the recommendations in their SOPs once the guidance has come to force.
Main focus of the guidance:
The guidance is divided in sections and contains all the necessary information to help decide whether a DMC is necessary and how to set it up and operate with it. We will visit the content in details in our next publication. Below is a high-level view of the structure and content of the draft guidance:
Background
The draft guidance describes the background in the use of Data Monitoring Committees so far.
Background
The interactions of the DMC with other oversight groups
- IRBs,
- Steering Committees,
- Endpoint Adjudication Committees,
- monitors, safety reviewers and
- Adaptation Committees
DMC establishment and operation
The following topics are visited:
- The composition of the DMC in terms of:
- membership
- conflict of interest
- training requirements
- The DMC Charter describing the following:
- composition of the DMC
- meetings schedule and format
- planned analyses
- confidentiality of the data
- The responsibilities of the DMC are described as:
- Monitoring of the trial conduct
- Monitoring of interim results in terms of
- safety
- effectiveness
- futility
- potential adaptations
- Consideration of external data
- Recommendations and documentation thereof
- The interim data and analyses including:
- Confidentiality of interim data
- Interim reports to the DMC
- Analysis used by the DMC
Independence of the DMC
“Independence is established when members have no involvement in the design or conduct of the trial or in the endpoint determination except through their role on the DMC or the adjudication committee.”
FDA recommendations for regulatory reporting
“Consistent with 21 CFR 312.32(d)(1), the sponsor must investigate a DMC’s recommendation relating to such safety events as potentially reportable to FDA under 21 CFR 312.32.”
In Ethical’s view, the FDA's proposed updates to the Data Monitoring Committees Guidelines promise to positively impact clinical development by promoting ethical, efficient, and participant-focused research, ultimately supporting expedited development of efficient treatments for patients.
The final guidance will be posted on Ethical’s website once it is finalized and officially published by the FDA. As always, Ethical’s team will align tools and procedures with the latest regulations to effectively support clinical trial sponsors in the ever-evolving clinical development landscape. For more information on Ethical’s eDSMB® tool, please visit https://www.edsmb.com
