The basis of pharmacovigilance is provided by the exchange of Individual Case Safety Reports (ICSRs) between the recipient of the original report and other interested parties, which include Marketing Authorization Holders (MAHs) and Health Authorities (HAs). Different regulators have different reporting requirements for report transmission. This results in replication of each ICSR that will exist in multiple locations. Adding in the fact that each case will go through multiple versions, different recipients may receive different case versions at different times, potentially influencing patient safety decisions and potentially amplifying or obscuring safety signals inappropriately.

The present study aimed to investigate the magnitude of replication, the variability among recipients, and the subsequent divergence across recipients of ICSRs.

Seven participating TransCelerate Member Companies (MCs) queried their respective safety databases covering a 3-year period and provided aggregate ICSR submission statistics for expedited safety reports to an independent project manager. As measured in the US Food and Drug Administration (FDA)’s Adverse Event Reporting System (FAERS), ICSR volume for these seven MCs makes up approximately 20% of the total case volume. Aggregate metrics were calculated from the company data, specifically: (i) number of ICSR transmissions, (ii) average number of recipients (ANR) per case version transmitted, (iii) a submission selectivity metric, which measures the percentage of recipients not having received all sequential case version numbers, and (iv) percent of common ISCRs residing in two or more MAH databases.

The analysis reflects 2,539,802 case versions, distributed through 7,602,678 submissions. The overall mean replication rate is 3.0 submissions per case version. The distribution of the ANR replication measure was observed to be very long-tailed, with a significant fraction of case versions (~ 12.4% of all transmissions) being sent to ten or more HA recipients. Replication is higher than average for serious, unlisted, and literature cases, ranging from 3.5 to 6.1 submissions per version. Within the subset of ICSR versions sent to three recipients, a significant degree of variability in the actual recipients (i.e., HAs) was observed, indicating that there is not one single combination of the same three HAs predominantly receiving an ICSR. Submission selectivity increases with the case version. For case version 6, the range of the submission selectivity for the MAHs ranges from ~ 10% to over 50%, with a median of 30.2%. Within the participating MAHs, the percentage of cases that reside within at least two safety databases is approximately 2% across five databases. Further analysis of the data from three MAHs showed percentages of 13.4%, 15.6%, and 27.9% of ICSRs originating from HAs and any other partners such as other MAHs and other institutions.

Replication of ICSRs and the variation of available safety information in recipient databases were quantified and shown to be substantial. Our work shows that multiple processors and medical reviewers will likely handle the same original ICSR as a result of replication. Aside from the obvious duplicate work, this phenomenon could conceivably lead to differing clinical assessments and decisions. If replication could be reduced or even eliminated, this would enable more focus on activities with a benefit for patient safety.