Department of Clinical Medicine (Pharmaceutical Medicine), Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
PLoS One. 2019 Jun 14;14(6):e0218534. doi: 10.1371/journal.pone.0218534. eCollection 2019.
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.
药品的剂量是通过临床开发和批准审查过程根据临床试验结果确定的；然而，在批准前从临床试验中获得的信息是有限的。一些药品的使用剂量低于批准的上市后使用剂量。本研究旨在揭示药品上市后临床使用的低剂量处方的实际情况。我们根据治疗领域、批准剂量的详细说明、临床数据包和上市后要求，调查了与偏差相关的因素。在 2005 年 1 月至 2014 年 12 月期间在日本批准的新分子实体中，如果有任何产品，我们确定了这些产品是口服的，并且对于不同的适应症具有相同的每日剂量。对于这些产品，我们从 Medical Data Vision Co.，LTD.和 JammNet Co.，LTD 的医学信息数据库中收集了实际每日剂量的信息。如果在 2015 年，≥30%的处方中的剂量低于批准剂量（初始剂量除外的维持剂量），则将产品定义为“低剂量处方药物”。在调查的 113 种产品中，我们确定了 27 种低剂量处方药物。多变量分析的结果表明，与解剖治疗化学分类和批准剂量详细说明相关的因素显著影响低剂量处方的发生，而与临床数据包和上市后要求相关的因素则没有。这些结果表明，基于批准前进行的临床试验获得的信息，确定药物实际临床应用的最佳剂量存在局限性，强调了在必要时重新审查适用于更多患者的最佳剂量的重要性。我们相信，真实世界数据的利用可以在这方面提供帮助。
