Abstract
The dosage of pharmaceuticals is determined through the process of clinical development and approval review based on clinical trial results; however, the information obtained from clinical trials before approval is limited. Some pharmaceutical products are used at doses lower than those approved for post-marketing use. The aim of this study was to reveal the actual state of lower-dose prescriptions for post-marketing clinical use of pharmaceuticals. We investigated the factors related to the deviation based on therapeutic area, detailed statement of the approved dosage, clinical data package, and post-marketing requirement. Among the new molecular entities approved in Japan between January 2005 and December 2014, we identified products that are orally administered and have the same daily dose for different indications, if any. For these products, we collected information on the actual daily dose from the medical information databases of Medical Data Vision Co., LTD. and JammNet Co., LTD. Products whose dose was lower than the approved dose (maintenance dose excluding the initial dose) in ≥ 30% prescriptions in 2015 were defined here as “lower-dose prescription drugs.” We identified 27 lower-dose prescription drugs out of 113 products investigated. The results of the multivariate analysis revealed that factors related to the Anatomical Therapeutic Chemical classification and the detailed statement of the approved dosage significantly influenced the occurrence of lower-dose prescription, whereas the factors related to clinical data package and post-marketing requirements did not. These results suggest the limitation in determining an optimal dosage for the actual clinical use of a drug based on the information obtained from clinical trials conducted before approval, emphasizing the importance of reexamining the optimal dosage that is applicable to a greater number of patients after marketing, if necessary. We believe that the utilization of real-world data could be of help in this regard.
Highlights
The determination of drug dosage is one of the important aspects for the effective and safe usage of pharmaceuticals
Defined daily dose (DDD), an average daily dose for adults in the primary indication defined by the World Health Organization (WHO), was changed in the post-marketing phase for 115 products between 1989 and 2000, and approximately 60% of them indicated a change to a lower dose [2]
This indicates that the dose of approximately one-third or more prescriptions was lower than the approved dose among the 113 products approved in Japan between 2005 and 2014. We believe this borderline can be one of the criteria for reconsidering the approved dosage to be applicable to a greater number of patients. This finding is consistent with the results reported previously, that is, approximately 20% of 449 new molecular entities (NMEs) approved between 1980 and 1999 in the United States were subjected to dose change after approval, with approximately 80% of the changes involving switch to a lower dose [1], and approximately 60% of the products whose WHO DDD was changed between 1982 and 2000 was changed to a lower dose [2]
Summary
The determination of drug dosage is one of the important aspects for the effective and safe usage of pharmaceuticals. Lower-dose prescriptions in the post-marketing scenario process of clinical development and approval review based on the results of clinical trials. It has been reported that the approved dose of approximately 20% of the new molecular entities (NMEs) in the United States between 1980 and 1999 was changed in the post-marketing phase and that the change to a lower dose due to safety issues accounted for approximately 80% of the overall changes [1]. It has been reported that a lower-dose prescription is often recommended for the elderly population and for reducing side effects [3,4,5,6], clinical evidence on using such a low dose is not reflected in the product label (package insert), even if it is published in medical journals [7,8]
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