Exploratory Analysis of Associations Between Postmarketing Safety Events and Approved Doses of New Drugs in Japan

Abstract

While efficient and less onerous for the industry, the globalization of clinical drug development may lead to limited efforts to optimize drugs for regional conditions. We examined the association between clinical development pathways, approved doses, and postmarketing safety risks in Japan for 135 new molecular entities approved between 2004 and 2011. The risk of drug-related deaths seemed higher when pharmaceutical companies chose exactly the same dose as in the United States, even after conducting Japanese dose-ranging studies. We also found a positive association with drug-related deaths when the review process was expedited and when Japanese dose-ranging studies were not conducted for nonexpedited drugs. Our findings suggest that the decisions on regional dose settings and the choice of global clinical development pathways are associated in ways that may influence the postmarketing outcomes in the target populations.

Figure 1

Distribution of median dose ratios (MDRs) (Japanese dose/United States dose). Boxplot with whiskers with maximum 1.5 interquartile range. Any data not included between whiskers are plotted as an outlier with a dot. (a) MDR by approval year. (b) MDR by therapeutic category. (c) MDR by nationality of license holders. (d) MDR by regulatory status. CNS, central nervous system.