Traditionally, Data Safety Monitoring Boards (DSMBs/DMCs) and Clinical Events Committees (CECs) have been set up to operate independently from each other. They have distinct functions and as such, membership generally does not overlap. However, since the FDA has no explicit regulatory requirement for the establishment of a DSMB/CEC (except in the case of emergency research conducted under 21 CFR 50.24 (a)(7)(iv)), it raises the question as to whether or not it may be feasible or even advantageous to combine their efforts into one safety monitoring board. To explore this option, consider the following Q&A’s:
What is a “traditional” Data Safety Monitoring Board or Data Monitoring Committee (DSMB/DMC)?
- “A group of individuals with pertinent experience that reviews on a regular basis accumulating data from one or more ongoing trials. The DSMB advises the sponsor regarding the continuing safety of trial subjects and those yet to be recruited to the trial, as well as the continuing validity and scientific merit of the trial.” Furthermore, it is a group of experts external to the trial and independent of the sponsor whose principal mandate is to protect patient safety. The primary responsibilities of the DSMB are to periodically review and evaluate the accumulated study data for subject safety, study conduct and progress, and if appropriate, efficacy.
- A committee who may be delegated by and independent of the sponsor whose purpose is to adjudicate research endpoints by providing a standard, systematic, independent and unbiased assessment of endpoints. They adjudicate individual adverse events within a study to determine if those events are possibly related to the study or investigational product or not. As with DSMBs, they share the responsibility of clinical safety monitoring and oversight, but they do not typically comment on overall study safety.
What regulations or guidance are available to reference in regards to DSMBs/CECs?
- In cases of exceptions from informed consent requirements for emergency research where the informed consent requirements are waived, these studies require “establishment of an independent monitoring committee to exercise oversight of the clinical investigation” (21 CFR 50.24 (a)(7)(iv)). Additionally, the Code of Federal Regulations indirectly references data safety monitoring in 45 CFR 46.111(a)(6) which states: “When appropriate, the research plan makes adequate provision for monitoring the data collected to ensure the safety of subjects.” There is also a 2006 guidance document available from the FDA titled “The Guidance for Clinical Trial Sponsors - Establishment and Operation of Clinical Trial Data Monitoring Committees”. This document “discusses the roles, responsibilities and operating procedures” of DSMBs. It is intended to assist with determining the need and set up of a DSMB. Again, with the exception to what is noted above, there are no formal regulations that govern DSMBs and CECs to date.
Are there circumstances where it would be acceptable for a board/committee to serve the traditional functions of both a DSMB and CEC?
- While this would not appear to be in violation of any FDA regulation, an individual’s participation in either group, or a blended group combining the functions of a DSMB and CEC, may have the potential to introduce bias into the study. For example, participation in a group which combines both DSMB and CEC functions (cumulative safety review and individual endpoint adjudication) may provide access to un-blinded data (DSMB function) that would not normally be available to a CEC. Furthermore, there may be facility, IRB, and/or local policies or requirements regarding DSMBs and CECs to be considered.
When the regulations are silent and do not directly point to a path for a study’s safety monitoring needs, the sponsor, IRBs, institutions, and investigators are free to develop processes that they feel are in the best interest of their research. A best practice for the sponsor to follow would be to discuss the establishment of safety monitoring groups with the appropriate FDA review staff during study protocol development and review.
Are you aware of or have you worked with a blended functions DSMB/CEC group? If so, were there any specific difficulties to work through, conflicts, or drawbacks?Question everything via photopin (license)