Analysis of Global Drug Development Pathways and Postmarketing Safety in Japan: Local Studies May Reduce Drug-Related Deaths

Recent International Conference on Harmonization (ICH) guidelines provide pharmaceutical companies with regulatory justifications to pursue various global drug-development pathways, in some of which "local" dose-ranging and/or pivotal phase III studies are skipped. We examined the association between the clinical development pathway and postmarketing safety in Japan for 177 new molecular entities approved between 2004 and 2013 focusing on dose setting histories for each drug. The risk of drug-related deaths was higher when companies did not conduct local (i.e., Japanese) dose-ranging studies and/or pivotal studies. Even when local dose-ranging studies were conducted, the risk remained higher in some drugs for which the approved dose in Japan was set equal to that in the United States. Drugs developed under a bridging strategy tended to show lower risks. These results suggested that local clinical studies may play a substantial role in achieving optimization of postmarketing drug use in each local target population.