The Japanese Pharmacopoeia (JP) is promoted internationalization in line with globalization of supply chain for pharmaceuticals. For example, harmonization of test methods and monographs is conducted by Pharmacopoeial Discussion Group (PDG) which consists of JP, the United States Pharmacopeia (USP), and the European Pharmacopoeia (Ph. Eur.). In addition, utilization of JP as a reference pharmacopoeia in Asian region is aimed by the Ministry of Health, Labour and Welfare and Pharmaceuticals and Medical Devices Agency of Japan. Therefore, to clarify characterization of JP comparing with USP and Ph. Eur. utilized worldwide is useful for harmonization activity in PDG and getting all users to use JP appropriately. Then, we compared the three pharmacopoeias about constitution, general notices which are fundamental to understand pharmacopoeia and status of provision on control of impurities which is one of the highest interest in the area of pharmaceutical quality. As a result, although the constitution among three pharmacopoeias was not completely same, their basic concept that the test methods and monographs are described in assuming following the general notices was common. In addition, all three pharmacopoeias stated comprehensive rule in general notices. The comparison also clarified that JP uses a term of “Being specified separately” in the general notices 11 to describe a relationship with approval documents, but USP and Ph. Eur. didn’t have such a provision. Furthermore, Ph. Eur. and USP had more chapters for control of impurities than JP. In consideration of these similarities and differences among three pharmacopoeias and characteristics of JP, we expect that JP will be not only enriched its contents but also more convenient for users.

We examined the time-to-onset of interstitial lung disease, cerebral hemorrhage, and gastrointestinal hemorrhage in very elderly patients with atrial fibrillation treated with direct oral anticoagulants (DOACs) by using data from the Japanese Adverse Drug Event Report Database (JADER). We compared the time-to-onset of each adverse drug reaction (ADR) based on age or dose for each DOACs. The median values of the time-to-onset ranged from 40 to 124 days for interstitial lung disease while those for gastrointestinal hemorrhage ranged from 60.5 to 91 days, they were no significant difference between the age or drug-dose groups. For cerebral hemorrhage, the median values ranged from 124.5 to 331.5 days, therefore the time-to-onset of cerebral hemorrhage was delayed compared to that of gastrointestinal hemorrhage. Especially, the median value of the factor Xa inhibitors (FXA) high dose (HD) and age 80≤ group showed 331.5 days, which was delayed compared to that in the FXA low dose (LD) and age 80≤ group’s 143 days or the FXA HD and age <80 group’s 175 days. The cerebral hemorrhage occurred not less than a year after dosing, and therefore symptoms of cerebral hemorrhage and continuous symptom management of hypertension need to be carefully monitored in not only early stage but also late treatment stages in FXA HD and age 80≤ patients. This study showed that the analysis using JEDAR could enhance understanding of the time-to-onset of ADRs in very elderly, which were difficult to be collected in clinical trials during drug development. Furthermore, it was suggested that time-to-onset of each ADRs was independently occurred. These findings contribute to grasp time-to-onset of the ADRs and appropriate management of ADRs in the clinical practice.

Gene-testing technology has dramatically advanced in recent years, and it now provides a simple and relatively affordable way to test the genetic makeup of individuals. In addition to genetic testing at medical institutions, companies now provide a DTCGT (Direct-to-Consumer Genetic Testing) system, which allows consumers to undertake a genetic test directly without visiting a medical institution, resulting in an expansion of the available services that predict potential diseases. Today, most DTCGT tests are not performed under the supervision of a registered physician or trained medical professional, which is both a medical and an ethical issue, and there is no suitable established regulation for DTCGT testing. Here we compare genetic testing rules and regulations in Japan, the U. S. and Europe (the UK, Germany, and France). We note that there are established laws and regulations governing the DTCGT system in most western countries, whereas in Japan there is guidance but no rules or regulations. To clarify the current situation in Japan, we surveyed the organizations that use the DTCGT system both in person and over the internet. We found that most of the 112 organizations using the system did so without supervision of a registered physician or trained medical professional supervision. We also identified genetic-testing results diagnosing disorders that actually needed suitable medical gene counseling. We conclude that the timely implementation of appropriate laws and regulations is necessary to solve these issues arising from the rapid expansion of DTCGT use in Japan.

This study investigated the prescriptions in which generic substitutions ware not allowed by prescribers. Among 75,513 prescriptions received by 233 pharmacies which belonged to Iwate pharmaceutical association during any one week from January to March, 2017, there were 7,926 prescriptions (10.50%) in which generic substitutions were not allowed. The number of drug items that were not allowed to be substituted ware 1,714, and a cumulative total number of drugs were 17,536. 52.70% of them was the brand-name drugs whose generic drugs were available in the market, and 14.86% of them were generic drugs for which particular product names were indicated. Classified by efficacy, cardiovascular agents, central nervous system agents, and digestive organ agents consisted of top 3 efficacies. Regarding reason why generic substitutions were not allowed, “patient’s request” was mostly indicated, then “prescriber’s preference” and “poor disease control or side effect caused by a drug substitution” were also indicated. In order to promote the use of generic drugs, it is necessary to reduce the number of prescription in which prescribers refuse the generic substitutions. For that, it is necessary not only to improve the quality of generic drugs and providing appropriate information about generic drugs but also to reform the prescription issuing system and the medical treatment fee system. Further studies are needed to survey the prescriptions in which prescribers refuse the generic substitution in other areas and to explore the effect of the generic substitution refusal on the use promotion of generic drugs.

Platelets have an essential role in hemostatic plug formation and wound healing. Platelet transfusions are widely indicated for patients with severe thrombocytopenia, and the clinical demand is rapidly increasing. Platelet concentrates used for platelet transfusions are currently supplied by volunteer donors. Due to their short shelf life (4 days in Japan and 5 days in the US), however, donor-dependent platelet concentrates are often insufficient in the supply. Recently, a line of evidence supports the clinical application of platelets to accelerate wound healing. However, it is difficult to use peripheral platelets for wide-range wound. Thus, new strategies for manufacturing MKs and subsequently platelets from a donor-independent source are urgently needed. We have established human adipose-derived mesenchymal stromal/stem cells (ASC) as cell source to generate platelets for transfusion medicine and wound healing. The use of ASC has an advantage in manufacturing platelets, because (1) establishment of ASC and its differentiation into platelets do not require gene transfer, and (2) megakaryopoiesis and thrombopoiesis are dependent on endogenous thrombopoietin.

In recent years, the clinical application of regenerative medicine using stem cells has been heralded as a new approach to the treatment of cerebral infarction. Our translational researches about bone marrow stromal cells (BMSC) transplantation for stroke was supported by Initiative for Accelerating Regulatory Science in Innovative Drug, Medical Device, and Regenerative Medicine, which is the fund from Ministry of Health, Labour and Welfare in Japan, from 2012. Our on-going clinical trial, Research on Advanced Intervention using Novel Bone marrOW stem cell (RAINBOW) study, is a phase Ⅰ study for acute ischemic stroke and the first subject was enrolled in June 2017. Autologous BMSCs were cultured with human platelet lysate (PL), instead of fetal calf serum (FCS), in the cell processing center. The cells were transplanted around the infarct stereotactically. In advance, the donor cells were labeled with superparamagnetic iron oxide (SPIO) for cell tracking using MRI. After the transplantation, ¹⁸F-fluorodeoxyglucose (FDG) PET and ¹²³I-Iomazenil SPECT were performed for the analysis of cellular function and brain metabolism. We expect that our study will evolve the autologous BMSC transplantation for stroke into the next generation. In the present article, we report our experience from the point of view of mechanisms of actions and therapeutic strategy, nonclinical studies, and subject screening in the clinical trials.

The cellular or tissue based products manufactured from mesenchymal stem cells out of various organs and tissues are being under clinical trials. Upon initiating the trials, the safety of these cell products in humans must be estimated in advance by conducting nonclinical safety studies. To date, several technical guidelines and the guidance on nonclinical safety assessment of the cellular products have been issued by the regulatory agency in Japan. In principle, the assessments of general toxicity, tumorigenicity and potential effects on vital organs (i.e., central nerve, respiratory, cardiovascular system) as well as safety evaluation of impurity exposure need to be carried out before the first clinical trial. Due to the restriction of study plans or interpretation of results caused by the immune response to the human cells in animals, the aims of the studies should be hazard identification rather than determination of NOAEL or estimation safety margin. The studies should also be planned on a case-by-case basis while taking into account the cell source, its character and complexity in the manufacturing process. This article provides the overview of general considerations for planning the study design of general toxicity and tumorigenicity and assessing the safety of central nerve, respiratory organ, cardiovascular system and impurity exposure.