Interstitial Lung Disease as an Adverse Drug Reaction in Japan: Exploration of Regulatory Actions as a Basis for High Reporting.

INTRODUCTION: Increased post-marketing reports of interstitial lung disease in Japan have been recognized. An understanding of its regional groundings can be important for the global pharmacovigilance community. OBJECTIVE: The objective of this study was to explore the correlation between high rates of interstitial lung disease reporting and regulatory actions in Japan. METHODS: Post-marketing interstitial lung disease-related label changes and interstitial lung disease reports were classified by the anatomical therapeutic chemical classification groups of the suspected drugs. Regulatory actions for the top interstitial lung disease-reporting drugs were compared. The interstitial lung disease reporting patterns of protein kinase inhibitors were compared to those of methotrexate. RESULTS: Interstitial lung disease-related label changes predominantly occurred for drugs in the anatomical therapeutic chemical classification groups L, J, C, and herbal medicines. Interstitial lung disease was reported most frequently for L group, especially for the protein kinase inhibitors. The regulatory actions for those drugs with the highest number of interstitial lung disease reports (methotrexate, protease kinase inhibitors, gemcitabine, docetaxel) plus monoclonal antibodies were analyzed. The ratio of interstitial lung disease reports to all reports over time was initially high in the re-examination period, while it was constantly low after the period expired. The increase in interstitial lung disease reporting was observed for the drugs for which interstitial lung disease was designated as a priority item in the use-results survey. Methotrexate had more interstitial lung disease reports with multiple suspected drugs and fewer reports with high completeness than the protease kinase inhibitors. CONCLUSIONS: The high rates of interstitial lung disease reporting derived from mainly the anatomical therapeutic chemical classification group L drugs. Interstitial lung disease is the targeted adverse drug reaction in the use-results survey mandated in the re-examination of those drugs. This system provides at least one explanation for the high reporting of interstitial lung disease in Japan.

Data-Driven Identification of Adverse Event Reporting Patterns for Japan in VigiBase, the WHO Global Database of Individual Case Safety Reports.

INTRODUCTION: Adverse event reporting patterns vary between countries, reflecting differences in reporting culture, clinical practice and underlying patient populations. Japan collects about 60,000 domestic adverse event reports yearly and shares serious reports with the World Health Organization (WHO) Programme for International Drug Monitoring in VigiBase, the WHO global database of individual case safety reports. Understanding these reports in the global context can be helpful for regulators worldwide and can aid hypothesis-generation for Japanese-specific vulnerabilities to adverse drug reactions. OBJECTIVE: The objective of this study was to explore differences in the reporting of adverse events between Japan and other countries. METHODS: vigiPoint is a method for data-driven exploration in pharmacovigilance. It outlines data subsets, pinpoints key features and facilitates expert review, using odds ratios subjected to statistical shrinkage to distinguish one data subset from another. Here, we compared 260,000 Japanese reports in E2B format classified as serious and received in VigiBase between 2013 and 2018 with 2.5 million reports from the rest of the world (of which 51% are from the USA). Reporting patterns for which the 99% credibility interval of the shrunk log-odds ratios were above 0.5 or below - 0.5 were flagged as key features. The shrinkage was set to the vigiPoint default corresponding to 1% of the size of the Japanese data subset. As a sensitivity analysis, additional vigiPoint comparisons were performed between Japan and, in turn, Africa, the Americas, the Americas except the USA and Canada, Asia and Europe. RESULTS: There were higher reporting rates in Japan from physicians (83% vs. 39%) and pharmacists (17% vs. 10%). It was also more common to see reports with more than five drugs per report (22% vs. 14%) and with a single adverse event (72% vs. 45%). More than half of the Japanese reports had a vigiGrade completeness score above 0.8 compared with about one in five from the rest of the world. There were more reports than expected for patients aged 70-89 years and fewer reports for adults aged 20-59 years. Adverse events reported more often in Japan included interstitial lung disease, abnormal hepatic function, decreased platelet count, decreased neutrophil count and drug eruption. Adverse events reported less often included death, fatigue, dyspnoea, pain and headache. Drugs reported more often in Japan included prednisolone, methotrexate and peginterferon alfa-2b. Drugs reported less often included rosiglitazone and adalimumab as well as blood substitutes and perfusion solutions. The findings were generally robust to the sensitivity analysis except for the less often reported drugs, many of which were rarely reported in most countries, except in the USA. CONCLUSION: Analysis of Japanese adverse event reporting patterns in a global context has revealed key features that may reflect possible pharmaco-ethnic vulnerabilities in the Japanese, as well as differences in adverse event reporting and clinical practice. This knowledge is essential in the global collaboration of signal detection afforded by the WHO Programme for International Drug Monitoring.

Analysis of safety-related regulatory actions by Japan's pharmaceutical regulatory agency.

PURPOSE: To evaluate the safety-related regulatory actions implemented by Japan's Pharmaceuticals and Medical Devices Agency (PMDA) in 2012. METHODS: We analyzed serious safety issues appended to drug package inserts (PIs) in Japan in 2012. The issues were characterized according to drug class, adverse event, years since drug approval, initiator of regulatory actions, revised section of PI, and evidence source. We also quantified the durations from signal detection to tentative decision and from tentative decision to regulatory action. RESULTS: We identified 144 serious safety issues during the study period, and the majority of evidence originated from spontaneous reports (83.5%). The PMDA initiated regulatory actions for half of all safety issues, and the median duration from drug approval to regulatory action was 8 years (interquartile range [IQR], 3-26.5 years). The median duration was 49 days (IQR, 0-362 days) from signal detection to tentative decision and 84 days (IQR, 63-136 days) from tentative decision to regulatory action. Several safety issues involving older drugs and multiple products had protracted decision-making durations. CONCLUSIONS: Most safety issues led to prompt regulatory actions predominantly based on spontaneous reports. Some safety issues that were not easily detected by the spontaneous reporting system were identified years after approval. In addition, several safety issues required assessments of multiple drug products, which prolonged the decision-making process.