# Longitudinal Descriptive Analysis of Dynamic Changes in Safety Concerns in Japanese Risk Management Plans for Medicinal Products Over 8 Years After Approval

## TL;DR

This study analyzed how safety concerns for drugs in Japan evolved over 8 years after approval, showing that most initial concerns remained and new ones were added.

## Contribution

The study provides the first longitudinal analysis of dynamic changes in Japanese risk management plans for medicinal products.

## Key findings

- Most initial safety concerns remained in RMPs 8 years after drug approval.
- New safety concerns were added, and some potential risks were upgraded to identified risks.
- Pharmacovigilance activities were the main source of evidence for RMP updates.

## Abstract

A Japanese risk management plan (RMP) is a proactive planning tool for managing safety concerns (important identified risk [IIR], important potential risk [IPR], and important missing information [IMI]) for each drug and is continuously updated. However, no studies have examined the dynamic changes of safety concerns in RMPs throughout the drug lifecycle.

We conducted a longitudinal descriptive analysis of safety concerns in RMPs of drugs approved for new active ingredients in 2014 in Japan. We compared safety concerns in RMPs between the first version at approval and the latest version 8 years after the approval date using the Sankey diagram. We also investigated the evidence for RMP changes.

This analysis included 38 drugs, whose first version RMPs included 155 IIRs, 119 IPRs, and 59 IMIs. Among them, all IIRs and 88% of the IPRs and the IMIs remained in the latest version of the RMPs 8 years after the approval date. During follow-up, 29 IIRs, 20 IPRs, and 3 IMIs were newly added, 14 IPRs were upgraded to IIRs, and 7 IMIs were deleted; thus, the final numbers of IIRs, IPRs, IMIs were 198, 125, and 55, respectively. Evidence for RMP changes was more often obtained from pharmacovigilance activities than from clinical/non-clinical studies conducted for additional approvals.

Most of the safety concerns identified at the first approval remained over 8 years, and the number of IIRs and IPRs tended to increase after approval. Most of the RMP changes were based on pharmacovigilance activities.

The online version contains supplementary material available at 10.1007/s43441-025-00801-2.