Postmarket safety communications on drugs approved in Japan: A 25-year analysis

Abstract

Drug safety communications (DSCs) are essential tools for communicating important postmarket serious drug safety information to healthcare professionals and patients. Previous studies characterized DSCs issued by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA); however, knowledge about the activities of the Pharmaceuticals and Medical Devices Agency (PMDA)/the Ministry of Health, Labor and Welfare (MHLW) is limited. This study characterized DSCs by the PMDA/MHLW in comparison with previously reported DSCs by the FDA and the EMA. We retrospectively analyzed 37 DSCs of 41 adverse drug reactions (ADRs) for 33 drugs in Japan from 1997 to 2022. Most DSCs were related to non-oncology drugs (30/37, 81.1%), and the median (interquartile range) time from approval to DSC issuance was 19 (10-51) months. Notably, the regulatory review reports and the latest labels before DSC issuance did not describe 16/28 (57.1%) and 12/37 (32.4%) of the ADRs related to DSCs, respectively. Most DSCs resulted in label revisions (36/37, 97.3%) and seven drugs were eventually withdrawn. Some DSC characteristics are similar among the PMDA/MHLW, the FDA, and the EMA; however, the number, contents, and range of new safety issues addressed by DSCs differ among the three jurisdictions. Our study emphasized the importance of continuous efforts to gather postmarket drug safety information because substantial ADRs that led to DSCs were recognized after approval and were associated with critical label revisions and withdrawals. Future studies are required to address global challenges for regulatory harmonization of safety-related regulatory actions.

FIGURE 1

Differences between the Yellow Letter and the Blue Letter in Japan. (a) The frequency of the issuance of drug safety communications (DSC) by years demonstrated no consistent trend. The Blue Letter was first issued in 2002, and the majority of DSCs were issued as the Blue Letter afterward. (b) The number of prescribed patients by DSC issuance was not different between the Yellow and Blue Letters for all DSCs; however, these patient numbers were larger for the Yellow Letter drugs than for the Blue Letter drugs after introducing the Blue Letter category. (c) The time from approval to the DSC issuance was not different between the Yellow Letter and the Blue Letter for all DSCs and for those issued after introducing the Blue Letter category. BL, Blue Letter, DSC, drug safety communication.