View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Springer - Publisher Connector Drugs - Real World Outcomes (2015) 2:227–237 DOI 10.1007/s40801-015-0034-5 ORIGINAL RESEARCH ARTICLE Using Clinical Databases to Verify the Impact of Regulatory Agency Alerts in Japan: Hepatitis B Testing Behavior After an Alert Regarding Risk of Viral Reactivation 1 2 3 1 Yukio Udagawa • Shinya Ohno • Shintaro Nakagawa • Kazutaka Sugimoto • Joji Mochizuki1 Published online: 13 August 2015 Ó The Author(s) 2015. This article is published with open access at Springerlink.com Abstract A to D: 4.70 % (n = 262/5571), 5.78 % (n = 330/5710), Background Measures of the effectiveness of risk mini- 6.52 % (n = 398/6101), and 7.59 % (n = 479/6315). mization activities are necessary for the appropriate use of However, no changes were observed in the rates of HBsAg drugs, and clinical databases are a low-cost method of and HBcAb/HBsAb testing (around 50 and 70 %, respec- quickly producing such results. tively). Overall testing rates appeared to differ depending Objective The aim of this study was to explore the sec- on disease and drug type. ondary application of clinical databases in verifying the Conclusion These findings suggest that the PMDA alert impact of risk minimization activities; specifically, whether was effective at recommending HBV-DNA testing. This such databases could be used to identify changes in hep- secondary application of clinical databases may be effec- atitis B virus testing behavior after an alert from the tive for verifying the impact of risk minimization activities. Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. Methods Patient data from December 1, 2010 to Key Points November 30, 2012 were extracted from the Medical Data Vision clinical database. The percentages of patients tested We used a clinical database to investigate the for hepatitis B virus DNA (HBV-DNA), hepatitis B surface relationship between a PMDA alert and changes in antigen (HBsAg), and hepatitis B surface antibody monitoring behavior for hepatitis B infection in (HBsAb)/hepatitis B core antibody (HBcAb) were com- patients receiving immunosuppressive agents. We pared 1 year before (consecutive 6-month periods A and B) also investigated this relationship in subgroups and 1 year after (consecutive 6-month periods C and D) a stratified by type of disease or immunosuppressive PMDA alert regarding viral reactivation in patients drug. receiving immunosuppressive agents. Results Data for 9866 patients in the clinical database Results indicated that a clinical database could be were analyzed. After the PMDA alert, the percentage of used to quantitatively verify the impact of risk patients tested for HBV-DNA linearly increased in periods minimization activities like this alert, which could support implementation of future risk minimization activities and verification of their impact. & Yukio Udagawa [email protected] Although the use of clinical databases to measure the effectiveness of risk minimization activities in 1 Drug Safety Division, Chugai Pharmaceutical Co., Ltd., 1-1 pharmacovigilance is necessary for the appropriate Nihonbashi-Muromachi 2-Chome, Chuo-ku, Tokyo, Japan use of drugs, the use of clinical databases is not yet 2 Project and Lifecycle Management Unit, Chugai common in Japan. We expect this study to encourage Pharmaceutical Co., Ltd, Tokyo, Japan similar research in the future. 3 Clinical Development Division, Chugai Pharmaceutical Co., Ltd, Tokyo, Japan 228 Y. Udagawa et al. 1 Introduction alert and changes in hepatitis B testing behavior for patients receiving immunosuppressive agents. The PMDA alert recommended that ‘‘when administer- As more clinical databases become available for general ing drugs with immunosuppressive effects, healthcare use, researchers are exploring a variety of potential new professionals should carefully observe patients’ signs and applications. Recent studies have used clinical databases to symptoms related to hepatitis B virus growth by monitor- verify the impact of drug risk minimization activities [1–3]. ing results of liver function tests or hepatitis virus mark- Several such studies have investigated the effects on hep- ers’’. This alert was a suitable target to examine the atitis B screening in cancer patients undergoing potential for using clinical databases to verify the impact of chemotherapy. Hanson et al. comparatively investigated distributing information to the medical community. Doc- the percentage of cancer patients tested for hepatitis B tors aware of the alert when prescribing immunosuppres- surface antigen (HBsAg) and hepatitis B core antibody sive agents would presumably then perform regular (HBcAb) at the onset of chemotherapy in the US before screening (such as HBsAg testing) and monitoring (such as and after the publication of clinical care guidelines [1]. HBV-DNA testing) according to Japanese HBV guidelines Hwang et al. similarly reported the changes over time in [6, 7]. The percentage of patients tested for HBsAg or the percentage of cancer patients tested for HBsAg and monitored for HBV-DNA would be expected to increase. HBcAb when starting chemotherapy in the US [2]. In These changes in testing status would be reflected in Japan, Ikeda et al. used an administrative health insurance databases such as the Medical Data Vision (MDV) clinical claims database to compare the implementation of hepatitis database, which includes the results of HBsAg testing in B screening tests before and after the publication of Japa- Japan. nese hepatitis B virus (HBV) guidelines in cancer patients This study aimed to clarify whether a pharmaceutical receiving chemotherapy for the first time [3]. company can use a clinical database to quantitatively verify Measures of the effectiveness of risk minimization the impact of risk minimization activities such as health activities are necessary for the appropriate use of drugs [4]. authority alerts, which could support future implementation Using clinical databases for this purpose is a relatively low- of risk minimization activities and verification of their cost method and provides rapid results. The drug safety impact. departments of pharmaceutical companies are most often responsible for verifying the impact of drug risk mini- mization activities; however, thorough verification is rare, 2 Methods with communication usually limited to a one-way flow of information to the medical community. After developing 2.1 Study Design the capacity to utilize clinical databases, researchers at Chugai Pharmaceutical Co., Ltd (Chugai) investigated their This cohort study used the MDV clinical database to utility in databases verifying the impact of risk minimiza- investigate patients prescribed immunosuppressive agents. tion activities. To identify changes in testing behavior, the status of In October 2011, Japan’s Pharmaceuticals and Medical patient testing for HBV markers was investigated during Devices Agency (PMDA) issued an alert regarding the risk two consecutive 6-month periods before (A and B) and of hepatitis B reactivation with immunosuppressive agents after (C and D) the PMDA alert (Fig. 1). [5]. However, no studies to date have used a clinical This study was conducted using a hospital claims data- database to investigate the relationship between the PMDA base stored in hospital electronic information systems Fig. 1 Four observation periods before and after a Pharmaceuticals hepatitis B in patients treated with immunosuppressive agents before and Medical Devices Agency (PMDA) alert. This study investigated and after an alert from the PMDA whether any change could be confirmed in laboratory testing for Verifying the Impact of Regulatory Alerts 229 constructed by Medical Data Vision Co., Ltd (MDV; (b) The percentage of NR patients tested for HBsAg Tokyo, Japan). The MDV database covers approximately before beginning immunosuppressive agent treat- 8.14 million patients in 153 hospitals across Japan, with ment, the percentage of these patients who were bed numbers ranging from 20 to more than 1000, and HBsAg negative, and the percentage of HBsAg- including about 10 % of all acute phase hospitals, except negative patients tested for HBcAb or hepatitis B university hospitals. The database uses a diagnostic pro- surface antibody (HBsAb). cedure combination payment system/per-diem payment system and comprises anonymized patient identifiers 2.4 Statistical Analysis attached to data on sex, birth year, department visited, date of medical service, diagnosis codes, hospitalization status, Patients receiving immunosuppressive agents were com- medical procedures, test orders, operations, and prescrip- pared before and after the PMDA alert to check whether tions [8]. the rates of hepatitis B testing increased. Patients receiving During the study, the authors did not access any patient immunosuppressive agents are defined as patients receiving data in the MDV clinical database. MDV performed and any of the immunosuppressive agents listed in Table 3 supplied the results of aggregate analysis based on the ‘‘Appendix’’ at least once during each period (A–D). analysis items and methods in the study protocol. On the basis of the protocol for this study (approved by the Seisenkai Matsumoto Clinic Institutional Review Board on 2.2 Subjects September 19, 2014, according to Japanese ethical guideli- nes for epidemiologic research [9]), MDV conducted Patients in the MDV clinical database who were already aggregate analysis of snapshot data from