Program

PO3-11-8

Conducting local dose-finding studies may help reduce post-marketing drug-related deaths

[Speaker] Tomoko Kawamura-Okubo:1
[Co-author] Shunsuke Ono:1
1:Laboratory of Pharmaceutical Regulatory Science, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan

Background: ICH-E5 guideline in 1998 has provided pharmaceutical companies with development options to extrapolate foreign clinical data in new drug applications data package and skip local dose-finding study in Japan. In line with the trend of globalization, the approved dose in Japan has become increasingly identical to the approved dose in the US. However, it is unclear whether these changes in drug development and approval have had substantial impact on drug safety. In this research we studied whether dose setting decisions and clinical development pathways had any association with post-marketing safety risks in Japan.
Methods: We examined the association between the presence of dose-finding studies, clinical development pathways, approved doses and post-marketing safety risks in Japan for 178 new molecular entities approved in both countries between 2004 and 2013. We applied the negative binomial regression model and then performed a propensity score-matched analysis to adjust for backgrounds of drugs.
Results: The risk of drug-related deaths was higher when pharmaceutical companies did not conduct local dose-finding studies. Even when local dose-finding studies were conducted, the higher risk seemed to remain when the approved dose in Japan was set equal to that in the US. The absence of local dose-finding studies was not associated with safety risks in cases where development pathways involve bridging strategies. Some other backgrounds of drugs and companies were also associated with safety risks. The approved dose ratio between Japan and the US did not show a clear association.
Conclusions: Our findings suggested that the decisions on regional dose settings and the choice of global clinical development pathways are associated in ways that may influence the post-marketing drug safety in the target populations. The drugs for which local dose-finding studies were conducted tend to have lower safety risks, although causal association is not simple. Pharmaceutical companies and regulatory authorities probably need to achieve the right balance between the efficiency of drug development process and the level of optimization of drug use in each local population.

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