Objective: Medical information databases provide useful Real World Evidence (RWE) and a comprehensive view of medical activities. However, since each database has limited coverage and cannot be self-sufficient, combining information from multiple databases is a useful research technique. In this study, we examined methods of estimating patient numbers by combining information from multiple databases in order to assess the respective databases and identify the respective characteristics, biases and idiosyncrasies. This process also allowed us to propose improvements in the grand design of medical information databases in Japan.
Design: Retrospective observational cohort study
Methods: We attempted to estimate the numbers of patients treated for certain diseases and the numbers prescribed a drug by three methods: i) We estimated patient numbers for seven diseases using an insurance claims database, adjusting the proportion of elderly patients according to a hospital medical records database; ii) Sales information for drug X was combined with the prescribed volume per person estimated from pharmacy claims databases to estimate the number of patients administered X; this number was divided by the prescription rate obtained from a medical claims database to calculate patient numbers for the associated disease; and iii) We examined two surveys of the National Institute of Infectious Diseases (NIID) for timely estimation of patient numbers for influenza, referring to estimates from an insurance claims database.
Results: In Method i)-iii), we proved that it is possible to estimate patient numbers for many diseases and administered drugs by effectively combining multiple medical information databases. Validation could be claimed when multiple methods lead to similar results.
Conclusion: These databases provided by government agencies and private corporations are separately managed, and there is no grand plan to integrate them into one platform. It is crucial that databases, rather than being designed to stand alone, are standardized according to widely used systems under a solid master data management strategy. This will make it easier to combine information from multiple databases and to maximize their values. Mutual use of these databases by academic researchers for epidemiological and clinical studies and by government policy makers and data scientists of pharmaceutical companies may improve the usefulness of these databases and expand their application in research.

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As for spontaneous case reports of suspected adverse drug reactions, the following problems are known, a part of phenomenon actually recognized to be side effects in clinical site is reported, moreover, the thing which report bias which fluctuate produces by a factor with the various rates exists, since an appearance ratio is incalculable, it cannot be adapted in the analysis technique for common side-effects data. Therefore, the search algorithm analyzing method of signal detection has been established. Japanese Adverse Drug Event Report database (abbreviation; JADER) is exhibited from Pharmaceuticals and Medical Devices Agency (abbreviation; PMDA) to April 2012, and can use anyone now without restrictions. It is expected that the quality of research of pharmacoepidemiology will improve by practical use of JADER. However, as for the present condition, there are few reports of the practical use example in a pharmaceutical company as a subject which tends to attract attention from “signal detection” as the practical use method, consequently regulatory agency should cope with. Although the pharmacoepidemiology group of the author Japanese Society for Biopharmaceutical Statistics is not comprehensive before public presentation of JADER, the list obtained by “case report line list search with which side effects are suspected” which PMDA offers was collected and put in a database, and practical use in a pharmaceutical company has been tried by referring to the examination method of pharmacoepidemiology. This paper explains the processing method of the JADER data for enabling signal detection. Using this method, application to the subject of much pharmacoepidemiology is performed actively, and it expects to contribute to improvement in the quality of research of pharmacoepidemiology.

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Japanese Adverse Drug Event Report database (Abbreviation; JADER) was disclosed April 2012 and will be expected to have a major role in the establishment of the adequate information for the proper usage of drugs. In this paper, we were compared using the shape parameters that were estimated by fitting the Weibull distribution, whether the adverse drug reaction of suicide- or diabetes-related onset time profiles vary depending on the type of interferon formulations. The data were used JADER of August 2013. The combined number of adverse drug reaction and drug that duplicates removed was 702,925. In diabetes-related side effects, the distribution of adverse drug reaction time was different among formulations. The shape parameters of the Weibull distribution are 1.49 (1.09-1.94), 0.84 (0.66-1.05) and 1.07 (0.92-1.23)(point estimates and two-sided 95% confidence interval) in interferon-α,-β and peginterferon, respectively. Interferon-α is categorized as the wear-out failure type adverse drug reaction onset time profile from which its 95% confidence interval exceeds 1. Peginterferon is classified as the random failures type from which its point estimates is almost 1. Since the upper 95% confidence interval is near 1, the time profile of interferon-β is close to the early failures type. We conclude that the combination of the shape parameter of the Weibull distribution and the visual inspection, like histogram and box plot, is useful in the monitoring of adverse drug reaction onset time profile.

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From April 2012, Japanese Adverse Drug Event Report database (JADER) has become downloadable for utilization in the public, under the specified acceptable use policy. Given the situation, we focused on the severe eruptions which cases are increased in the public Relief System for Sufferers from Adverse Drug Reactions, for the purpose to analyze the characteristics of typical severe eruptions and a trend or a commonality in the corresponding reported drugs, by utilizing JADER. Disproportionate reporting obtained with ROR (Reporting Odds Ratio) and distribution parameter estimations obtained with Weibull distribution fit for the onset time of drug adverse reactions, were applied for the analysis in addition to the summary of frequency. We obtained 10,171 cases of severe eruptions from JADER, after exclusion of duplicated reports. In the Drug Induced Hypersensitivity Syndrome (DIHS), which has characteristics in clinical time course and causal drugs, we confirmed that typical causal drugs such as anti-epilepsy are frequently reported in JADER. On the other hand, drugs other than typical causal drugs also showed high ROR signal values. In the estimation of Weibull distribution shape parameter fit for drug adverse reaction onset time, DIHS gave estimation apparently different from other severe eruptions. Coincide with the estimation, histogram of onset time for DIHS showed the peak at around 20 days after drug administration, which is later than other severe eruptions. We conclude that analytical approach to obtaining information from multiple aspects of JADER data should be a useful effort for the persons who are engaged in preventive action for drug adverse reactions.

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The new practical use example of the JADER datasets from Japanese Adverse Drug Event Report database opened by Independent Administrative Agency Pharmaceuticals and Medical Devices Agency in April, 2012 and afterwards will be reported. The purpose of this study is to examine the evaluating method of medicine concomitant use risk by the frequency at which two or more medicines were reported simultaneously, being assumed the possibility of the influence of drug interactions to be the concomitant use risk in an adverse drug event onset. In order to estimate the potential degree of the safety risk at the time of the concomitant use, the methodology was estimated by the following procedures. 1) For considering that two suspicion medicine targeted is one medicine, the statistical signal index which means those of medicines with use in the case where they both are indicated in one report, the index of the concomitant use, is computed. 2) The statistical signal index about two target suspicion medicines is computed individually. 3) The case where the ratio of the index of the concomitant use to the index obtained individually exceeds 2 also in any of two suspicion medicines is judged as there being the concomitant use risk. The Proportional Reporting Ratio (PRR) and the Reporting Odds Ratio (ROR) were used as a statistical signal index. In order to check the validity of this method, Stevens-Jonson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) which are known for the adverse events of critical drug rash reported in JADER were taken up, and the causality of medical supplies limited to the medicine with which they were reported as a suspicion medicine. As for the combination of the suspicion medicine which fulfills the conditions of the concomitant use risk, 10 kinds of candidates out of 159 combinations for SJS and 22 kinds of candidates out of 111 combinations for TEN were detected, respectively. Although this approach for the concomitant use risk was considered to be an effective means in showing the above results, some issues about the ratio of the index of the concomitant use and criteria in the report numbers of the medicine to be chosen, the effective calculation method for combinations in more than 3 medicines, etc. will be required for the further examination.

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From pharmacovigilance point of view in Japan, individual case safety reports from industries are important evidence when authorities make decision regarding safety issues, e.g., package insert change. On the other hand, aggregate analysis is not majority due to less infrastructure of available large database than EU/US. Japanese Adverse Drug Event Report database (JADER), which ICSRs have been cumulated, has been tried to use for aggregate analysis. It is not appropriate to use for the purpose of signal management or for primarily deriving safety measures, considering that its source does not cover all the safety information but “spontaneously reported serious adverse reaction”. However, it would be worthwhile to use JADER as a virtual tool to become able to utilize coming large EHR DB and National Claim Database which the authorities have been constructing to be available within few years.

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A Task Force team consisting of members from pharmaceutical companies --a central player to develop and implement RMP (Risk Management Plan)-- as well as health care professionals and members from academia was established in JSPE. The Task Force developed guidance for scientific approach to practical and ICH-E2E-compliant Pharmacovigilance Plan (PVP) stated in Japanese Risk Management Plan issued in April 2012 by the Ministry of Health, Labour and Welfare. The guidance contains the following topics.
1．Introduction: JSPE's activities and this task force's objectives for pharmacovigilance activities
2．How to select Safety Specification (SS) and describe its characteristics
・Selection of SS
・Characterization of SS
・Association with Research Questions (RQ)
3．How to define and describe RQ
・What is RQ ?
・RQ interpretation in other relevant guidelines
・Methodology to develop RQ for PVP with examples
・Best approach to integrating PVP for whole aspects of safety concern
4．How to optimize PVP for specific RQ
・Routine PVP or additional PVP ?
・Additional PVP design (RQ and study design, RQ structured with PICO or GPP's research objectives, specific aims, and rationale)
・Checklist to help develop PVP
5．Epilogue:
・What can/should be “Drug use investigation” in the context of ICH-E2E-compliant PVP.
・Significance of background incidence rate and needs for comparator group
・Infrastructure for the future PVP activities
6．Appendix: Checklist to help develop PVP activities in RMP
The task force team is hoping that this guidance help develop and conduct SS and PVP in accordance with ICH E2E, as stated in Japanese Risk Management Plan Guideline.

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Since the Vol.1 No.1 was published in March 1996, the journal of “Pharmacoepidemiology” has been published approximately two times per year. The current issue is Vol.18 No.1 in 2013. The number of original articles in total was forty-three. Based on these original articles, what type of pharmacoepidemiological studies were performed and the trend of study designs are demonstrated. The studies for database and methodology of pharmacoepidemiology have been constantly conducted. The number of the studies for evaluating drug usefulness and drug utilization is decreasing. In contrast, the studies for evaluating drug safety is increasing, especially, hybrid designs, such as a case-crossover study or nested case-control study are recently conducted.

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