International Medicinal Product Information Documents: A Quantitative Content Analysis of Instructions for...

Medicinal product information documents (PIDs) detail clinical characteristics and instructions for monitoring, preventing, and mitigating adverse drug reactions (ADRs). They vary across countries, but there have been no recent international comparisons. We have therefore quantified and compared the completeness of the information given in drug labelling from different countries.

From the websites of 35 regulatory agencies, we retrieved the PIDs of medicinal products that were involved in signals communicated by regulators in 2014-2019. We developed a data extraction framework based on the Dose-relatedness, Time course, Susceptibility (DoTS) clinical classification of ADRs and used its implications for prevention and mitigation to score the completeness of related instructions in PIDs. To extract and classify monitoring instructions, we used a modified Systematic Instructions for Monitoring (SIM) method. PIDs had sufficiently complete instructions for prevention when the DoTS score was ≥ 5/12, and sufficiently complete monitoring instructions when the SIM score was ≥ 3/6. We used proportions of PIDs having a score ≥ 1 to determine the relative availability of clinical characteristics or instructions in a country, compared with all other countries. We quantified their pairwise disagreements using Jaccard's distance and identified clusters with similar patterns of completeness using agglomerative hierarchical clustering.

PIDs were available on the websites of 18 of 35 regulatory agencies. They concerned 364 distinct medicinal products, which were involved in 627 signals. Across all countries, the instructions for prevention or mitigation met sufficient completeness for a median of 30% of PIDs (IQR 28-33%), while instructions for monitoring were sufficiently complete for a median of 22% (IQR 19-25%). The information given by the European Union (EU) and Canada had the highest relative availability of clinical characteristics and prevention or mitigation instructions, with a proportion of 0.86. Canadian and EU PIDs also had the highest relative availability of monitoring instructions, with proportions of 0.79 and 0.70. Two clusters of countries showed low disagreements: Malaysia and Singapore; Australia and New Zealand.

This study suggests that PIDs often do not contain complete instructions for prevention, mitigation, and monitoring of ADRs. Extending existing regulatory cooperation globally would enable regulators to access clinical characteristics and instructions from different regions.