What Goes into a Charter for DSMB or Endpoint Adjudication?
After 20 years of supporting clinical trial sponsors, the team at Advarra knows success depends on having a good committee charter. Independent data monitoring committees (DMCs/DSMBs) and endpoint adjudication committees (EACs/CECs) rely on the charter to set the course for project and the conduct of the committees. All of them have one thing in common: Success depends on having a good committee charter.
Where the clinical protocol outlines clinical trial operations and conduct details, the charter does the same to guide the operations and actions of the associated DMC and/or EAC supporting the trial. This blog looks at the key elements of a good charter and explores why these details are critically important to the successful completion of the research.
Find out what DMCs and EACs do and the value they add for clinical research in our blog “DMC vs EAC: What’s the Difference“
A Note on the Regulatory Term “Charter”
In this blog, and in practice, we talk about a “charter” because that is the term the Food and Drug Administration (FDA) uses in its 2006 guidance on data monitoring committees, which governs how DMC and EACs operate. However, the charter document is also seen as an operating plan, operations manual, or similar instructions document describing how the DMC or EAC will independently oversee and assess the research as it is carried out.
Also, keep in mind, both FDA and European Medicines Agency (EMA) consider the charter to have the same level of importance as the clinical trial protocol itself. They can ask for the charter at any time, and they frequently do.
Why Have a Charter?
A charter is an important document required by the regulators, ranking right up there alongside the clinical protocol. To quote FDA, charters are required and are considered an essential document reviewable by the agency:
“Such charters are important for the same reason that study protocols and analytical plans are important—they document that procedures were prespecified and thereby reduce concerns that operations inappropriately influenced by interim data could bias the trial results and interpretation. … FDA may request that the sponsor submit the charter to FDA well in advance of the performance of any interim analyses, ideally before the initiation of the trial” FDA guidance “Establishment and Operation of Clinical Trial Data Monitoring Committees,” section 4.3
EMA has similar language in its 2005 guidance on data monitoring committees.
When to Complete a Charter?
DMC and EAC must be set up and operational prior to the protocol initiating, and a key part of the setup process is formulating the charter.
“A DMC [or EAC] has to be fully functional before enrollment into the study starts to enable it to respond to any safety signal.” EMA guidance “Guideline on Data Monitoring Committees,” section 4 (EAC reference added for context)
FDA’s guidance gives a bit more wiggle room than EMA’s, saying the DMC or EAC must be set up and operational prior to when the committee performs its analysis. However, keep in mind, the FDA also indicates they might ask for the charter as part of their protocol review under the investigational new drug (IND) or investigational device exemption (IDE) requirements.
You do not want to be caught flat-footed during a meeting with the regulator and not have a finalized charter in hand.
What Goes into a Charter?
The charter is the detailed operating plan for how your DMC or EAC will review and oversee the trial. It is the instruction manual, trial guide, statement of work, and blueprint all wrapped into one.
Without a detailed and well-defined charter, the committee may not know exactly what their review scope entails. Likewise, the sponsor may not know which events or what datasets to evaluate, along with the basis and framework for that evaluation.
The following is a partial list of information typically found in a charter:
- Detailed description of the committee’s responsibilities for the specific study (e.g., what events will be adjudicated, what statistical data will be seen, etc.)
- List of committee members, including their qualifications
- Declaration of any possible committee member conflicts of interest
- Description of communication procedures, including data flow between the sponsor and the committee and procedures for interacting with the sponsor and other relevant parties
- Responsibilities, timelines, and detailed description of how information will be formatted (e.g., tables, listings, and graphs for DMC; images, information, and Digital Imaging and Communications in Medicine [DICOM] standard for EAC) for the committee’s assessment, including methodological aspects of the review
- Frequency and format of committee meetings (open and closed meetings)
- Stopping rules, so the DMC is aware of the threshold for adverse events and can make a recommendation within the parameters that is agreed upon
- Documentation of the committee meetings (open and closed meetings)
At Advarra, we start each project with a template charter. We work collaboratively with the sponsor or contract research organization (CRO) to ensure all necessary areas are covered (in keeping with regulatory guidance), providing sufficient details in the charter so everyone knows the plan and execution process.
Of course, just like clinical trial protocols, charters can be updated and amended during the conduct of the trial as new information becomes available or additional adjudication events need to be included.
Value of Collaboration
One area many folks overlook is the importance of sincere collaboration when developing the DMC and EAC charters. It is critical the trusted third party who will administer your DMC or EAC takes time to listen, designing the charter to fit the protocol objectives and endpoints while also protecting participants and the safety and efficacy measurements.
Developing the charter is also a good time for the DMC and EAC expert medical and clinical research professionals to offer the sponsor suggestions for potentially incorporating more efficient or meaningful endpoints and measurements into the protocol. DMCs and EACs are there to provide unbiased independent oversight; they are also designed specifically to provide the sponsor with advice and guidance.
A Solid Charter: More Than Just a Good Idea
Anyone involved with clinical research for any period of time knows the process of conducting a clinical trial requires a lot of planning, protocols, operating procedures, and charters to map out what will happen, who will do what and when, and the expected outcomes and results. Without a solid DMC or EAC charter document to map out the details, potential chaos might ensue. Not only is it necessary, but regulatory agencies also mandate charters.
It’s best to work with a trusted third party willing and eager to collaborate with you on DMC and EAC charter development, which will help move your research forward in a positive and timely manner.