Age and multimodal safety assessments: limitations of spontaneous reports data and the importance of advancing age-based risk stratification capabilities in real world data

Background: Spontaneous reports data are routinely used for drug and vaccine safety surveillance and have known limitations, including the non-random nature of data collection. Surveillance strategies that rely primarily on spontaneous reports data are therefore not well-suited to examine whether risks are differentially distributed by certain types of risk, such as age.

Objectives: To evaluate the ability to identify a drug-outcome association that is known to differ by age (i.e., anticholinergics and the risk of falls and fractures, which is higher among older adults) using a multimodal surveillance approach.

Methods: Overall, and among patients 18-64 and > 65 years old, associations between falls and fractures and anticholinergics were assessed using the Food and Drug Administration’s Adverse Event Reporting System (FAERS), a spontaneous reports database, and separately, in the TriNetX Global database derived from a federated network of de-identified electronic health records (EHR). Disproportionality analyses with Multi-item Gamma-Poisson Shrinker (MGPS) model were used to evaluate associations in FAERS, overall, and stratified by age. In TriNetX using a 1-month surveillance windows post anticholinergic index date, differences overall, by age groups, and among patients with overactive bladder (OAB) were assessed with risk ratio (RR) estimates with 95% confidence intervals (CI). Statistical alerts overall, and by age, were based on the following criteria: for MGPS, if the lower limit of the 90%CI is higher than 2; for age RRs, the lower bound of the 95%CI is greater than 1.

Results: In real world data (RWD), our findings confirm a known age difference in the incidence of falls and fractures among anticholinergic-treated patients, where older patients were found to have a higher risk compared to younger adults 1 month post-index (Older versus younger adults: falls RR=2.8, 95%CI(2.7-2.9); fractures falls RR=1.6, 95%CI(1.6-1.7)). Effect estimates for increased risks were consistently statistically significant for other longer duration surveillance windows, as well as among patients with OAB. In FAERS, there were no significant associations between anticholinergics and falls or fractures overall, or by age.

Conclusions: These analyses demonstrate the importance of developing a capacity to enable rapid and routine examination of safety outcomes by age using a multimodal surveillance approach. Age-stratified analyses using RWD, such as de-identified EHR in TriNetX’s Global Network database, with a dashboard that supports rapid data query analyses and default risk estimation by age, may provide insights into risk subgroups for drug- or vaccine-outcome pairs that may otherwise be missed if analyses of spontaneous reports data are solely relied upon.