Objective: The aim of this study was to evaluate the healthcare economic burden of nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH) who progress to liver cirrhosis (LC) and hepatocellular carcinoma (HCC) in Japan. Method: A retrospective study using the Japan Medical Data Center (JMDC) claims database which include data between 2005 and 2019, with a total of 185,121 patients enrolled, and 136,718 patients meeting the criteria for NAFLD/NASH, with 313 patients progressing to LC, and 146 patients progressing to HCC. The healthcare costs were calculated based on inpatient, outpatient, and pharmacy claims evaluated independently at NAFLD/NASH, LC, and HCC diagnosis. Result: Total all-cause healthcare costs per patient per month (PPPM) after diagnosis was lowest in the NAFLD/NASH cohort at ¥134,143, with ¥268,033 for LC (p<0.0001) and ¥345,156 for HCC (p<0.0001) being significantly higher. In addition, the post-diagnosis and pre-diagnosis costs are statistically different across each liver disease severity stage. Conclusion: This is the first study that has analyzed current cost burden in NAFLD and NASH patients in Japan from an administrative real-world claims database, which demonstrated the progression of advanced liver disease stages in NAFLD or NASH patients represents a significant economic burden.

Pediatric drugs are required worldwide, but their amounts are not clinically sufficient. We therefore examined the pediatric drug needs based on a survey of 6th year students who completed long-term practical on-site training at Shujitsu University between FY2017 and FY2019. The major prescribed drugs that the students prepared were antimicrobials, antiallergic drugs, central nervous system drugs, gastrointestinal drugs, and cardiovascular drugs. Preparing the drugs with a pediatric dosage and formulation was not difficult for the students. As there were many drugs without a pediatric dosage or formulation, the students sometimes prepared pediatric drugs from adult drugs. They felt difficulties during such training. To set the pediatric dose, body weight and age conversion were mainly selected. To make powders, they sometimes crushed tablets or capsules, but this may impact on the stability and bioequivalence of the drug products. According to the questionnaire survey, it was also difficult for the students to communicate with pediatric patients and their parents. As a result of questionnaires of students, pediatric drugs at a pediatric dosage and appropriate pediatric formulations are needed for pediatric drug development to reduce dispensing errors and to ensure the quality of pharmaceuticals.

The use of real world data (RWD) and real world evidence (RWE) is expected to have various advantages in drug development such as increase in efficiency of development, improvement of patients’ access to new drugs, and reduction in burdens of data collection on medical staff by using secondary data. However, the acceptability of RWD/RWE for regulatory purpose is still unclear in any countries including Japan and the US. We investigated regulations and regulatory authorities’ projects on RWD/RWE and cases of RWE use for drug approval in Japan and the US. Regulations and projects in Japan were for developing unapproved drugs and off-label use, the purpose of post marketing surveillance, and leveraging disease registry. In the US, the FDA provided a framework that will evaluate the use of RWD/RWE to support the regulatory decision making. The FDA has also been working on projects in collaboration with pharmaceutical and health data companies and academic institutions dealing with practical issues of RWD/RWE application. From the review of the cases in which FDA did or did not accept RWE as evidence to support the decision making on approval, key points on reliability and relevancy of RWE required for regulatory use were found. Furthermore, registry data or electronic health record (EHR) -derived data were commonly used for regulatory submission in the US, whereas in Japan, registry data were commonly used. In order to enhance the use of RWD/RWE for regulatory decision making in Japan, it is important to develop an environment where various data sources can be applied and to have a common view of the reliability of RWD/RWE.

The development of microphysiological systems (MPS) is accelerating in Japan, the United States and Europe aiming improvement of the drug development efficiency. MPS is an in vitro culture system in which a culture environment similar to that of a living body is reconstructed in a small compartment. MPS is a new culture method that combines engineering and cell culture technologies, and problems to be solved are pointed out from a perspective different from those of conventional culture technologies. Therefore, this paper outlines the expectations for social implementation of MPS and the challenges that need to be solved for regulatory acceptance.

In addition to the environment surrounding of the pharma industries (1) declining the productivity in research and development in pharma industries, (2) widespreadness of 3Rs in animal testing, and (3) emergence of new modalities, new approach methodologies (NAMs) are actively incorporated to benefit the patients by transformation of the cutting-edge science based on the concept of regulatory authorities. The microphysiological system (MPS) is expected as one of the candidates in NAMs. MPS generally refers to an in vitro culture system in which a culture environment close to that of a living body (in vivo) is reconstructed in a created minute space using a microfluidic device. Currently, many products have been put into practical use by US’s and Europe’s companies and are sold all over the world. This time, I would like to introduce the trends of research & development for MPS in global scale, the trends in the pharmaceutical industry regarding MPS in each region, and the status of global competition in regulatory science over MPS. I hope that this information will be an opportunity to start strategic discussions for regulatory science to quickly expand the utilization of the cutting-edge science for the value of patients and to think about the additional role of researchers in pharma industries.

Despite recent advances in life sciences and large investment in drug discovery research, the success rate of drug development remains low. Since safety accounts for a large percentage of failure of clinical studies, selection of compounds with fewer toxicity concerns is the key to improving the success rate of drug development. However, predicting clinical toxicity from preclinical studies, which mainly use animal models, is still challenging because of species differences. Recently, in vitro models using human cells have been attracting attention to overcome this issue. These novel in vitro models have physiologically relevant functions compared to cell lines traditionally utilized in in vitro assays, thereby enabling us to predict toxicity in humans with high accuracy. Additionally, with the high throughput, these models can be applied from early stages of drug discovery research, thus making it possible to select more promising drug candidates and focus research and development resources on them. In this review, we introduce in vitro models to predict cardiotoxicity and hepatotoxicity, which are two leading causes of clinical failure derived from safety issues.

In 2009, the ICH-S7B guideline was issued focusing on the non-clinical risk assessment for the QT interval prolongation of pharmaceuticals. After the issuance of the ICH-S7B guideline, the technique of culturing has been established for homogeneous myocardial cells (myocardial-like cells) from human iPS/ES cells with functions such as contraction similar to human myocardial tissue expressing ion channels that control heartbeat. These cells are readily available on a commercial basis. Research institutes in Japan and the United States have studied to apply these myocardial-like cells to cardiovascular risk assessment of pharmaceuticals. Human iPS-derived myocardial-like cell (iPS-CM) expressing ion channels that control the action potential of myocardium is validated to utilize for comprehensive proarrhythmia risk assessment. Currently, the ICH E14/S7B Implementation Working Group is discussing the requirements for using the test systems as part of nonclinical safety studies in New Drug Application. This article provides the usefulness in human risk prediction regarding cardiovascular safety evaluation using iPS-CM, which has a function similar to that of newly developed cardiomyocytes with human biological function. The points of consideration are also shown regarding the validation and interpretation of test results required when establishing a new assay system as regulatory studies.

In recent years, population pharmacokinetic and pharmacodynamic analysis has been increasingly utilized in drug development when considering pharmacokinetics, pharmacodynamics and exposure-response relationships. The population approach is useful for evaluating the pharmacokinetic profile of patients, comparing different population groups (e. g., between different ethnic groups), and to obtain the appropriate dosage and administration of drug. However, there was no guideline showing basic principles and detailed considerations for population pharmacokinetic and pharmacodynamic analysis in Japan. Thus, the “Guideline on Population Pharmacokinetic and Pharmacodynamic Analysis” has been developed in consideration of the latest accumulated scientific knowledge. In this article, we present an overview of the guideline and a development process of this guideline from standpoint as regulatory members in an industry-public sector-academia research group.