Coronary stent fracture (SF) is recognized as a risk of restenosis or stent thrombosis. However, the actual incidence is unclear in real world clinical settings in Japan. This study aims to estimate the incidence of SF in Japan by surveying peer-reviewed journals, and to elucidate the actual situation of adverse event reports. We conducted literature analysis regarding the incidence of SF using PubMed and ICHUSHI on April 1 2014. For PubMed, the term “stent fracture” was used. For ICHUSHI, “coronary artery” (in Japanese), “stent” (in Japanese), “fracture” (in English), “fracture” (in Japanese), and “damage” (in Japanese) were used. PubMed search initially yielded 895 papers. Of these, 792 studies had been conducted in countries outside of Japan, 45 studies were related to non-coronary artery, 17 studies did not deal with incidences of SF, and 11 studies targeted duplicated cases during the same implantation period. After these studies were excluded, we analyzed 30 remaining papers comprising 14 observational studies and 16 case reports. There were 643 SF cases in the scientific papers and 105 SF cases in the adverse event reports. Through the 14 observational studies, the SF incidence was estimated as 5.4% (595/10,927 lesions). We found a significant difference in SF incidences between the paper and adverse event report (6.1-hold). These data indicated that the adverse event report showed a partial picture of the real situation.

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We conducted a questionnaire survey on cancer patients and their family caregivers to reveal their information needs for palliative care. Also we conducted another survey to explore the current situation of information provision on palliative care through the website of cancer medical institutions. The information that the respondents would like to know most was “cost of hospitalization”, followed by “average waiting time” and “facility of ward and hospital rooms”. Regardless of the respondents’ age, 60% of them had accessed the website of the medical institution to get the palliative care information. Thirty percent of them had been dissatisfied with the information due lack of the information and specific contents. Therefore, improving the contents of the information on the website may increase patients’ satisfaction. Regarding the survey of the information provision on palliative care through the website of cancer medical institutions, we found that medical institutions with well-established treatment system such as palliative care team unit were more likely to have further improved information provision than the others. Though the percentage of medical institutions providing the information of medicines used in palliative care was under 30% in 2014, it was higher than that in 2012. Therefore, the situation will be improved in the future.

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Regulatory affairs committee of Japan Pharmaceutical Manufacturers Association (JPMA) performed questionnaire survey for member company to grasp pharmaceutical development status in Japan, a development strategic tendency and analyzed project number change, trend in projects, ratio of MRCT (the multi regional clinical trial) in each development phase, and pattern of clinical data package for projects in development/submission. As a result, the number of projects under development increased to 805 in 2014, from values in the past three years. In a little less than 40% projects is considered global simultaneous application, and this tendency was markedly seen with projects by MRCT conduct, and the importance of the MRCT strategy for the drug lag elimination was confirmed. In addition, the MRCT conduct ratio with the anticancer drugs was higher than in other therapeutic areas. We also confirmed that the ratio of MRCT increased in later phases in this investigation, but several projects involved global development from early stage, suggesting the development strategy in Japan became diversified. The MRCT strategy is expected to contribute the global simultaneous development in delivering an innovative medicine to the Japanese patients earlier.

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The promotion of in-home medical and long-term care is a priority in Japan, as the birthrate is declining rapidly and population aging continues. In areas in which in-home medical care services are provided, there are problems concerning medicine administration and storage. As pharmacotherapy experts, pharmacists are expected to participate in in-home medical care. Although their participation is increasing overall, many pharmacies do not provide in-home medical care services. This study examined the obstacles and solutions to promoting in-home medical care services provided by community pharmacists in metropolitan areas, where the enhancement of in-home medical and long-term care is urgently required. The hearing survey conducted in metropolitan areas revealed details concerning the circumstances surrounding problems such as lack of pharmacists, cooperation, and understanding of other medical staff. The results suggest that holding conferences on in-home medical and long-term care and promoting the activities of the Japan Pharmaceutical Association are effective in strengthening the cooperation between pharmacists and other medical staff. An analysis of 47 prefectural medical care plans showed that, to operate the plan-do-check-act (PDCA) cycle effectively, it is important to establish indices of status and numerical targets that reflect status accurately, such as the number of pharmacies that provide in-home medical care services. Furthermore, examination of the establishment of numerical targets related to cooperation is critical, because cooperation between pharmacists and other medical staff is a very important issue in promoting in-home medical and long-term care.

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US FDA strongly encourages drug applicants to consider the implementation and use of data standards for the electronic submission of nonclinical and clinical research data to FDA in advance of their requirement. With regards to nonclinical research data, Standard for Exchange of Nonclinical Data Implementation Guide (SENDIG) has been developed by the Clinical Data Interchange Standards Consortium (CDISC) in order to propagate understanding and implementation of Standard for Exchange of Nonclinical Data (SEND) by expanding and modifying the Study Data Tabulation Model (SDTM) that is originally used for clinical submissions. US Food and Drug Administration (FDA) is receiving SEND data sets prior to the official implementation in 2016, and many pharmaceutical companies are probably utilizing SEND for data warehouses. These represent a trend illustrating the important role SEND is playing from the viewpoint of business strategy. Under such circumstances, more pharmaceutical companies are required to establish strategic procedures on electronic submission of nonclinical data to FDA in order to avoid the potential risks in the course of SEND data set preparation and acceptance by FDA. This article provides a general overview of worldwide trends on SEND implementation, and discusses the necessary measures taken by pharmaceutical companies and Contract Research Organizations (CROs) in Japan.

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Human biospecimens with detailed clinical information is critical for drug discovery research, in order to augment advanced medical care. To obtain reliable results, it is advisable to use the human biospecimens centrally-stored by biobank. Establishment of biobank is increasingly becoming popular year by year in Japan. Although the preservation of the human biospecimens is actively performed, they are rarely utilized effectively in research. It is necessary to examine about the contents of the informed consent (IC), intellectual property rights of the research products, and the quality of the samples in order to construct delivery systems for human biospecimens. The Tsukuba Human Tissue Biobank Center (THB) was established at the University of Tsukuba Hospital in November 2013. THB accepts applications of providing samples with clinical data from researchers from industry and/or academia, and provides the samples after the research applications has been approved by ethical review committee in the University of Tsukuba Hospital. The document containing detailed information about THB obtaining IC from the patients is comprehensive. The ethical guidelines for medical research using of human biospecimens such as ethical guidelines for human genome/gene analysis research and ethical guidelines for medical and health research involving human subjects have recently been amended. The restrictions on the use of human biospecimens for medical research are less strict than they were earlier. Thus, biobanks are now easy to access. We hope that our approach for biobank would trigger development in the field of drug discovery.

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There still exists in Japan a persistent feeling which looks use of human cell or tissue for medical study as against human dignity. But such study serves people’s life, health and welfare. It is really for human dignity. At present, we do not have the law which applies to such study directly. In order to promote this kind of study in proper way, we should make clear and explicit rules, considering the existing laws, such as Act Concerning Dissection and Preservation of a Dead Body (1949), and Act Concerning Organ Transplantation (1997).

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For the selection of clinical candidate-compound in the early stage of drug discovery, it is important to estimate the human prediction from the results of efficacy and safety studies in experimental animals. The research and development studies by using human tissues are generally to be done for the purpose of screening the model system development, effective target defining as a medicine, and estimating the target distribution and function regarding efficacy and safety. Recently it has been clearly articulated that insufficient curative-medicine is existing in some disease areas such as the therapeutic medication of cancer and central nervous system, despite considerable diseases become curable or improvable in these ten years. Tremendous progress of science and technology in molecular biology and other scientific disciplines has led to have a better understanding the disease-biology and its mechanism. As a recent trend, following approaches have become an urgent issue in order to improve or get cured of obstinate diseases. ①Understanding the disease itself based on molecular biological genome-science and technology. ②Efficient biomarker setting for translation from pre/non clinical experimental data to clinical development research ③Selection of the right patient by using precise diagnosis. Basic consideration for improving/curing disease should take a direction toward the questions as follows : “Right target?” ; to identify right target and its role of cellular pathways, “Right molecule?” ; to identify molecule and optimize their properties, “Right patient?” ; to prove molecule efficacy and safety in indicated/selected patients. These processes would lead to precision medicine from one-size-fits-all through personalized medicine.

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It is essential to predict the pharmacokinetics (PK) of drugs in the process of drug development. Thus, to accurately predict the human PK before starting the clinical studies, the concept of in vitro-in vivo extrapolation (IVIVE) has been utilized. Since PK is determined as an output from detoxification system consisting of multiple metabolic enzymes and uptake/efflux transporters, it is difficult to predict the PK without in vitro experimental systems which maintain the expression of all the PK-related genes. Moreover, species differences in expression/function of those genes have to be considered. Therefore, it is very effective to use human-derived tissue samples for IVIVE. We have been involving many researches to clarify the impact of transporters on the in vivo PK with the use of human cryopreserved hepatocytes and kidney slices. We demonstrated that in vitro uptake clearances of transporter substrate drugs into human hepatocytes and kidney slices were well correlated with in vivo human hepatic (non-renal) and renal clearances, respectively. Moreover, by the use of probe substrates and inhibitors for each transporter isoform, we succeeded in the estimation of the relative contribution of each transporter to the tissue uptake of drugs. Regarding the prediction of drug interactions, though the decrease in the renal secretion clearance by the coadministration of cimetidine was believed to be due to the inhibition of organic cation transporter (OCT) 2, we proposed that the inhibition of renal efflux transporter, multidrug and toxin extrusion (MATE), should be a true target for drug interaction with cimetidine.

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Momentum toward the practical use of regenerative medicine in Japan has accelerated, with new laws and other policy measures enacted by the government. In the case of hair follicle regeneration, building on the findings of basic research using human tissues and cells, clinical research studies on autologous cell-based therapy for hair loss are ready to be conducted. In this article, we review the latest trends in cell-based clinical research on hair loss treatments, including the use of dermal sheath cup cells (DSCC), the mesenchymal cells of the hair follicle believed to have hair-inductive ability. We also outline legislation and requirements for cell processing facilities (CPC) needed for clinical application.

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Recent years, pharmacometric modeling and simulation (M&S) techniques have a key role at every stage of global clinical drug development, and the population pharmacokinetic (PPK) /exposure-response (ER) modeling and analysis outputs are also mostly involved in regulatory documents to be submitted during and post Japan NDA filing. In this paper, theoretical backgrounds in ER modeling are outlined to describe PK-exposures/clinical outcomes causal relationship in clinical database from randomized dose controlled trials (RDCT), considering how to handle confounding factors on causal relationship of PK-exposures/Clinical responses. Next, there are two important application examples, where ①GEE modeling approaches for time to variant exposure/efficacy variables and ②M&S extrapolation to pediatrics from adults are outlined. The GEE model provided reliable assessments on recommended dose selection and optimize study plan on the clinical endpoint. By the 2nd PPK/PD M&S, the pediatric clinical study was enabled to maximize Benefit-Risk ratios in target pediatric patients’ population. These typical PPK/ER approaches could provide highly informative outputs not only for clinical drug development, but also regulatory decision making. Furthermore, some additional consideration are forecasted in conclusion such as copula regression, chronological hierarchical bayes model, and biomarker covariates to manage more complicated clinical study design.

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The history of ICH (The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) has been passed for over 20 years and more than 80 ICH guidelines including scientific and technical guidelines regarding quality, efficacy and safety of new drugs and guidelines for submission dossier had been developed and harmonized. In addition to the guidelines, training activities are highly important in order to implement the ICH guidelines smoothly and facilitate to expand the ICH guidelines to non-ICH regions. This article summarizes such training activities in three ICH regions (US/EU/JP) and non-ICH regions and discusses how Japan can contribute further. Training activities of ICH guidelines are delegated to each region. In Japan, there were a variety of trainings organized by pharmaceutical industry not only by regulatory agencies. In EU and US, there were cases which nonprofit organizations such as DIA took a role of primary providers of training. In non-ICH regions, main providers of training had been each regulatory agency by around 2011. However, nonprofit organizations such as DIA and PIC/S became major providers recently. In Asia, APEC Harmonization Center has organized a number of trainings. In the meantime, there were examples that same trainings using common training materials developed by ICH were conducted globally for Q trio and E2 series guidelines. Under the circumstances that ICH activities are expanding to non-ICH regions, Japan should contribute to training further especially in Asia and globally. Then Japan should boost its presence as one of the founding ICH members.

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