Analysis of Safety-Related Regulatory Actions for New Drugs in Japan by Nature of Identified Risks

BACKGROUND: Mechanisms underlying safety events may be heterogeneous and depend on conditions of development and marketing, including the populations studied in clinical trials and the amount of data required for approval, especially under pathways for accelerated access. OBJECTIVE: This study was conducted to investigate possible factors affecting the first post-marketing safety-related regulatory actions (SRRAs) after launch of new drugs in Japan. METHODS: We studied 338 new molecular entities (NMEs) approved in Japan between 2004 and 2014. We focused on three different types of SRRAs: (1) all-SRRAs (i.e. SRRAs from domestic cases and other countries), (2) domestic-SRRAs (i.e. SRRAs from domestic cases) and (3) domestic unknown-SRRAs (i.e. SRRAs of unknown risks from domestic cases). Occurrences of the three types of SRRAs were analyzed using Kaplan–Meier analysis and Cox-regression. RESULTS: SRRAs tended to occur sooner for NMEs launched in recent years versus those launched towards the beginning of the study period. Risk of SRRA was high for antineoplastics. Drugs for cardiovascular diseases, central nervous system, and diabetes had positive associations with all-SRRAs, but the associations were weaker with domestic-SRRAs. Domestic-SRRAs were more likely for drugs with relatively novel modes of action (MOAs). Longer lag to Japanese launch after first global launch significantly lowered SRRA risks. While most of the variables showed similar associations across the three types of SRRAs, adoption of bridging strategies showed higher risks only for domestic-SRRAs, not for all-SRRAs. FDA safety labeling changes and non-orphan priority review drugs presented higher domestic-SRRA risks. The number of adverse drug reactions (ADRs) from spontaneous reports had positive correlations with the three types of SRRAs, whereas the number from company-led surveillance showed no association. CONCLUSIONS: Our results indicated that global clinical development pathways and marketing status should be considered more seriously in implementing locally optimized pharmacovigilance activities. Caution may be needed not only for drugs with novel MOAs, but also for drugs for which local dose-finding studies have been skipped, expedited review status has been given, timing of launch is close to those in the USA and the EU, and spontaneous reports rather than company-lead surveillance suggest possible safety risks.