[Relationship between Dose Discontinuation or Dose Reduction for Safety Reasons in Clinical Trials and Lower-dose Prescriptions in the Post-marketing Setting].

Abstract

Dosage of pharmaceuticals is determined and approved based on pivotal clinical trial results in Phase 3. However, in the post-marketing setting, it is often adjusted according to conditions of individual patients. Some pharmaceuticals are used at a lower dose than the approved dose for safety reasons or in elderly patients. In this study, we examined the relationships between dose discontinuation or dose reduction, for safety reasons as well as participation of elderly patients in clinical trials, and lower-dose prescriptions in the post-marketing setting. We collated the dataset of 113 eligible pharmaceuticals from those that were approved in Japan between 2005 and 2014. Subsequently, we calculated the proportions of patients who withdrew from the study, whose medication was discontinued, or dose reduced due to adverse events, and of elderly patients (over sixty-five years old) to those who were exposed to the approved dose range in the pivotal clinical trials. Then their relationships with lower-dose prescription in the post-marketing setting were examined using Mann-Whitney U test. The proportions of patients who withdrew from the study (p=0.0019), whose medication was discontinued owing to adverse events (p=0.0007), or whose dose was reduced owing to adverse events (p<0.0001) were significantly higher for lower-dose prescription drugs than those for other drugs; however, the proportion of elderly patients did not show this significant increase in the lower-dose prescription drugs group.