Design Diagram：A Framework for Visualizing Study Designs Using Real-world Data and Improving Study Reproducibility / 薬剤疫学

There is growing interest in generating evidence from routinely collected real-world data to support medical and regulatory decision-making. However, longitudinal study designs using real-world data are often complex, and text-only descriptions make it difficult for most readers to understand their designs. To address this issue, in 2019, experts from industry, government, and academia developed the “design diagram,” a framework for visualizing longitudinal study designs. The design diagram uses standardized terminology and a graphical structure to communicate study design details to readers, thereby improving reproducibility. Based on previous work by a joint task force between the International Society for Pharmacoepidemiology (ISPE) and the Professional Society for Health Economics and Outcomes Research (ISPOR), the diagram includes a comprehensive set of key study parameters related to reproducibility. It successfully presents study designs in an unambiguous and intuitive manner. Diagrams have been proposed for various study designs, including cohort, nested case-control, and self-controlled designs. Recently, a new diagram was developed that adds at-a-glance elements to show the observability of the source data used in the study. The use of design diagrams is recommended in both the ISPE/ISPOR-endorsed harmonized protocol template (HARPER) and in reporting guidelines for pharmacoepidemiological research, and its widespread use is expected. This paper describes the structure of the design diagram and provides examples of its use. Effective use of design diagrams is expected to improve the reproducibility and reliability of database studies.

Research Trends and Future Issues Related to Pre-analysis Data Preprocessing in Large-scale Real-World Data ―With the Goal of Using it in Clinical Research― / 薬剤疫学

In recent years, the utilization of health care databases has been increasing worldwide. It is expected that Real World Data (RWD) will soon be effectively used for clinical research in Japan. On the other hand, database studies that use accumulated existing data such as electronic medical records, Diagnosis Procedure Combinations (DPCs), and health insurance claims, require extremely high loads of data preprocessing before statistical analysis is possible. So far, there is insufficient literature that describes the challenges of RWD preprocessing from an academic point of view. In this review paper, the challenges of database study are classified into three categories：（1）data content,（2）data structure, and（3）large-volume data handling. We then investigated existing preprocessing research and systematically introduced them. Most data preprocessing research targeted the improvement and reliability of the database itself through supplementing data contents required for each clinical research. There is very little research with the primary purpose of solving problems related to data structures and large-volume data processing. As the use of RWD for clinical research increases, the importance of the data preprocessing field will be recognized. In the future, we expect to see more research focused on RWD, which can enable the growth of clinical researches using RWD.

Recommendations for Conducting Post-Marketing Database Study in Japan Based on the Critical Appraisal of Published Articles from Overseas Real-World Data (RWD) Analyses / 薬剤疫学

Real-world data (RWD), such as a health insurance claim database and electronic medical record database, which records daily medical care information, is one of the most important data sources in pharmacoepidemiological studies. In Japan, a post-marketing database study has been added as a new category of post-marketing surveillance since April 2018. It is expected that the post-marketing database studies will be conducted in the actual risk management plan； however, at this point, few have reached the stage of publishing study results. On the other hand, overseas, many database research results using RWD have already been reported. Although it is necessary to keep in mind that there are differences in the characteristics of the databases (e.g., data contents, structures) and the differences in the medical environment between overseas and Japan, we think that critically reviewing these reports has a reference value for the planning, execution, and interpretation of the results in performing post-marketing database studies in Japan. The purpose of this report is to examine the characteristics and cautions of the database studies through a critical review of published articles of overseas RWD studies and to make recommendations that are useful for conducting post-marketing database studies in Japan. We hope this article will become a help in the planning and implementation of future post-marketing database studies.

Recommendations for Conducting Post-Marketing Database Study in Japan Based on the Critical Appraisal of Published Articles from Overseas Real-World Data (RWD) Analyses / 薬剤疫学

Real-world data (RWD), such as a health insurance claim database and electronic medical record database, which records daily medical care information, is one of the most important data sources in pharmacoepidemiological studies. In Japan, a post-marketing database study has been added as a new category of post-marketing surveillance since April 2018. It is expected that the post-marketing database studies will be conducted in the actual risk management plan； however, at this point, few have reached the stage of publishing study results. On the other hand, overseas, many database research results using RWD have already been reported. Although it is necessary to keep in mind that there are differences in the characteristics of the databases (e.g., data contents, structures) and the differences in the medical environment between overseas and Japan, we think that critically reviewing these reports has a reference value for the planning, execution, and interpretation of the results in performing post-marketing database studies in Japan. The purpose of this report is to examine the characteristics and cautions of the database studies through a critical review of published articles of overseas RWD studies and to make recommendations that are useful for conducting post-marketing database studies in Japan. We hope this article will become a help in the planning and implementation of future post-marketing database studies.

Suspected adverse drug reactions reported for Brazilian children: cross-sectional study / Suspeitas de reações adversas a medicamento relatadas em crianças brasileiras: estudo transversal

ABSTRACT Objective: To assess spontaneous reports of suspected adverse drug reactions in children aged 0-12 years from the Brazilian Health Regulatory Agency between 2008 and 2013. Methods: A cross-sectional study on suspected adverse drug reactions reports related to medicines and health products in children was carried out for a six-year period (2008-2013). Year of report, origin of report by Brazilian state, gender, age, suspected drug, adverse reaction description and seriousness were included in the analysis. The data obtained was compared to the number of pediatric beds in health services and to global data from the VigiBase (World Health Organization). Results: A total of 3330 adverse drug reactions were reported in children in Brazil in the investigated period (54% were in boys). About 28% of suspected adverse drug reactions reports involved 0 to 1-year-old children. Almost 40% of reports came from the Southeast region. Approximately 60% were classified as serious events. There was death in 75 cases. Nearly 30% of deaths involved off-label use; 3875 medicines (465 active substances) were considered suspected drugs. Anti-infective (vancomycin, ceftriaxone, oxacillin, and amphotericin), nervous system (metamizole) and alimentary tract and metabolism medicines were more frequent in reports. Conclusions: The distribution of suspected adverse drug reactions reports by sex and age group corresponded to the profile of children hospitalized in Brazil. Data about seriousness and medicines reported may be useful to encourage regulatory actions and improve the safe use of medicines in children.

RESUMO Objetivo: Analisar relatos espontâneos de suspeitas de Reação Adversa a Medicamento (RAM) em crianças de 0 a 12 anos notificadas pela Agência Nacional de Vigilância Sanitária entre 2008 e 2013. Métodos: Um estudo transversal a partir de notificações de suspeitas de RAM relacionadas a medicamentos e produtos para a saúde em crianças foi realizado por um período de seis anos (2008-2013). O ano da notificação, a origem do relato por estado brasileiro, sexo, idade, o medicamento suspeito, a descrição da reação adversa e a gravidade foram incluídos na análise, bem como o número de leitos nos serviços de saúde e dados global da VigiBase. Resultados: Um total de 3330 reações adversas foram relatadas em crianças no Brasil no período investigado (54% em meninos). Cerca de 28% dos relatos de suspeitas de RAM envolveram crianças de 0 a 1 ano de idade. Quase 40% dos relatos vieram da região Sudeste. Aproximadamente 60% foram classificados como eventos graves. Houve ocorrência de morte em 75 casos. Quase 30% das mortes envolveram o uso off-label dos medicamentos. Um total de 3875 medicamentos (465 substâncias ativas) foram considerados fármacos suspeitos. Medicamentos anti-infecciosos (vancomicina, ceftriaxona, oxacilina e anfotericina), com ação no sistema nervoso (dipirona) e no trato digestivo foram os mais frequentemente notificados. Conclusões: As notificações de suspeitas de RAM por sexo e faixa etária corresponderam ao perfil de crianças hospitalizadas no Brasil. Os dados sobre gravidade e medicamentos relatados podem ser úteis para encorajar ações reguladoras e melhorar o uso seguro de medicamentos em crianças.

<b>3．For a Change of Pharmacovigilance Activities, from a Viewpoint of a Pharmaceutical Company </b> / 薬剤疫学

This article describes findings about effective utilization of electronic medical databases from a viewpoint of a pharmaceutical company, with a progress of MIHARI Project in mind. Purposes of this article are (1) to understand merits to perform a database study and a drug use result survey as an additional pharmacovigilance activity for each risk in a risk management plan, and (2) to find points to be considered when their activities are to be selected. A database study has advantages as follows: a comparison group can be set easily; a power is high as a database has many cases; and no need to consider some points such as reporting bias and recall bias. On the other hand, some issues of a technical point (e.g. understanding characteristics of each database) and a regulatory system (e.g. clarifying association to the drug reexamination system) should be considered. A drug use result survey has advantages as follows: data can be collected, even the data that databases do not have; and a drug use result survey in a specific condition can be useful. As a usual design of drug use result surveys however is hard to answer a research question on each risk, more various designs should be considered. Each pharmacovigilance activity has different points to be considered. Therefore, we have to clearly understand the purpose to perform an additional activity and select the most appropriate activity to maximize the benefit of medication users.