Table 3.

Problems and Vignettes Regarding Reporting and Monitoring SAEs/AEs in Clinical Trials Involving Seriously Ill Older Adults

Problem 1: Limited guidance Limited support to develop appropriate data safety monitoring plans (DSMP) consisting of appropriate defined, classified, and selected SAEs/AEs for a study context

a. An investigator seeks but cannot find guidance to define appropriate SAEs/AEs in their DSMP. As a result, the investigator includes SAEs/AEs that are commonly reported and suggests reporting of them in expedited timeframes, but these SAEs/AEs are either implausibly related, misaligned, or well known with the study population, setting, or intervention. Later, when a selected SAE/AE occurs in the context of the study, the event is not logically related but the research team nonetheless spends significant time filling out reporting forms and submitting single expedited reports in cases where aggregate reporting would be sufficient.  b. A DSMB member receives a notification each time an AE (e.g., fall) occurs in a large multi-sited study where falls are both expected for an older seriously ill population, unrelated to the study intervention, and if reported should be reported in aggregate. The DSMB member feels overwhelmed by the amount of data coming in and would like study investigators to be better informed on reporting criteria but does not know how to better prepare them for DSMB communications.

Problem 2: Inconsistent standards Different regulatory bodies that oversee research safety use different reporting standards, constructs, and thresholds

a. OHRP and FDA have a higher reporting threshold compared to DSMB, and each reporting body uses its own reporting timeline. An investigator, fearful of incorrectly reporting, over-reports or confuses reporting requirements, creating large volumes of irrelevant or incorrectly reported data and potentially drowns out safety concerns of interest.  b. Some regulatory bodies indicate that “expected events” must be listed in the study brochure or investigational plan at the outset of a study. A death (SAE) occurs in a study that was not previously documented as expected, but the investigator knows that it occurred as part of the study participant’s underlying disease condition. Since it was not previously documented in study materials as unrelated to study mechanisms, the investigator does not know whether it must be reported, to whom, or at what time-point.

Problem 3: DSMB knowledge gaps DSMB committees are designed to be comprised of topic and biostatistics experts, but there are gaps in their collective knowledge to evaluate a DSMP and set up appropriate monitoring structures and reporting timelines

a. DSMB requires a study team to conduct expedited individual reporting of all deaths that occur during the study, even though the investigator explains that some deaths will occur given the participants are in a late stage of disease. Repeated expedited reporting requires significant effort on the part of the research team and monitoring bodies, and will not provide the data to determine if there is enhanced safety risks to a treatment group. However, the DSMB composition does not seem to include experts in end-of-life care to support pragmatic reporting frequencies and timelines.  b. A health services researcher submits a DSMP for a trial to compare two electronic chart documentation strategies for ease of follow-up usage by front-line administrators. The investigator excludes from reporting patient-level AEs. A DSMB challenges this omission, and ultimately, the investigator adjusts the DSMP to report patient-level clinical AEs, even though they do not believe they can adversely affect patient outcomes through the study mechanisms.