Objective : “blue letter” is one of the warning measures about medicines in Japan. “blue letter” is issued by pharmaceutical company when the Japanese Ministry of Health Labour and Welfare (MHLW) judges to take safety measure after sale. The objective of this study is to research whether pharmaceutical company and MHLW found each Serious ADR reported by “blue letter” when each clinical trial was completed. When they discussed side effects before sale, we researched how they provide the information for health care workers. Method : With the medicines on which “blue letters” were issued between 2006 and 2015. We researched each review reports about side effects and whether pharmaceutical companies and MHLW noticed the side effect before sale. And we researched each label information about side effects and whether health care workers were able to get enough information on the side effect before “blue letters” were issued. Result and discussion : Between 2006 and 2015, 11 “blue letters” were issued. In 8 letters of 11 letters Pharmaceutical companies and the MHLW realized each side effects in clinical trial. And they provided each side effects information in each label information. But, most information was vague expression before “blue letter” was issued. We suggest that pharmaceutical companies release more specific information in drug labels as a communication tool. Conclusions : Many of pharmaceutical companies had provided side effect information before “blue letters” were issued. But it was not clear enough to change the medical professional`s behavior for patients.

This study aims to understand the current situation and discuss elements that would further promote the development of orphan drugs in Japan. We analyzed drug lags (approval lags) and designation lags on orphan drugs approved as new drug categories in Japan over the past 5 years from 2010 to 2014. As a result, many of orphan drugs were developed in Japan after they were established in the US and the EU, and one-fourth at the maximum were developed locally for Japan. Regarding drugs that were first approved in the US or the EU ahead of Japan, Japanese median drug lags behind the US and the EU (lags of drugs that were considered spontaneously developed by pharmaceutical companies are in parentheses) were 50.0 (25.1) months and 34.8 (20.4) months, respectively. While Japanese drug lag issue for new medicines has recently been resolved, it was revealed that a longer drug lag behind overseas still exists in orphan drugs field. Japanese median designation lags behind the US and the EU were 63.8 (30.6) months and 46.7 (30.0) months, respectively. With further analysis and consideration, the drug lag and the designation lag in Japan are considered significantly attributable to a lag in development initiation or application for orphan designation. We consider it necessary to discuss revision of the existing designation criteria, development fee grant system operational procedures, and provision of incentives, aiming resolution of a lag in development initiation or application for orphan designation and further promotion of orphan drug development in Japan.

Background : In 2016, the U. S. Food and Drug Administration issued a guidance entitled “Determining the extent of safety data collection needed in late-stage premarket and postapproval clinical investigations.” The approach this guidance proposes leads to reductions in costs and work time and may improve the quality of the study database. We evaluated the applicability of selective data collection for oncology drugs. Methods : Review reports of oncology drugs for Japanese new drug applications issued by PMDA were used for the present study. The frequencies of adverse events observed in the pivotal studies were paired and compared between the first approval and the supplemental approval. Paired studies were categorized into four groups ; A) same tumor type and same usage, B) same tumor type and different usage, C) different tumor type and same usage, D) different tumor type and different usage. Results : 31 study pairs that had obtained additional indications between 2009 and 2014 were investigated. In group A, all 5 pairs showed high correlation coefficients : r=0.8199, 0.7844, 0.7399, 0.7345, and 0.6370. Conclusions : Selective data collection should be adopted in cases in which the additional indication is for the same tumor type and usage as the first or previous indication.

Because software as a medical device (SaMD) does not come into direct contact with patients, it does not pose such direct harm as that caused by conventional hardware medical devices (non-SaMD) ; however, SaMD does present indirect harm. Using US recall data, the objective of this study was to investigate indirect harm caused by software medical devices including both SaMD and non-SaMD. We collected recall data in which the cause was determined by the US Food and Drug Administration to be software design, and we determined whether the product in each recall was SaMD or not (non-SaMD). We also classified the failure mode of each recall into four groups : physical (Group 1) ; information-related (Group 2), data-related (Group 3) ; and other (Group 4). We identified 6,393 recalls for 2009-2014, and 712 software-caused recalls. Of those, the leading failure mode was Group 2 that can lead to indirect harm and accounted for 408 (57%), followed by Group 1 that can lead to direct harm and accounted for 122 (17%). Of 408 Group 2 recalls, 387 (95%) were recall class Ⅱ and 6 (1%) were recall class Ⅰ. Of the 6, 4 were for non-SaMD and 2 were for SaMD. The findings revealed by this study indicate the importance of the further understanding of safety of information presentation functionality and the necessity of further discussion of safety measures.

Factors which affect the degree of price gap between the National Health Insurance (NHI) reimbursement price and the actual market price of new drugs at their first NHI drug price revision after being listed in the NHI price list was investigated. Three hundred and three New Active Substances were listed in the NHI price list between October 2004 and December 2014 in Japan. After excluding drugs which gained the premium to promote the development of new drugs and eliminate off-label use or were subject to re-pricing, 104 drugs were selected for this study. Price gaps between the NHI reimbursement price and the actual market price were calculated based on the first revised NHI reimbursement price for the targeted drugs after being listed in the NHI price list. The price gap of drugs with 4 competitors or more was larger than that of drugs with 3 competitors or less (p=0.0001). Periodic NHI drug price revision is a useful system to provide the opportunity to re-evaluate the market value of drugs and reflect the changes in the actual market price to its NHI reimbursement price. For better pharmaceutical market where manufacturers can gain a profit commensurate with the value of their products, we should continue to discuss price calculation and revision schemes that properly reflect the drug’s clinical value while improving the trade practice of pharmaceuticals.

Providing adequate consultation by pharmacists for OTC medication is important for both, the effective use of the drugs and consumer safety. The main information source for patients using OTC drugs is frequently the package insert, currently, and little information source is available for health professional. The aim of this study was to evaluate pharmacists′attitudes and concerns towards OTC drug package inserts via a survey. A questionnaire survey regarding available OTC drugs′information was conducted with 60 pharmacists working in hospitals (30) and pharmacies (30). The survey consisted of the respondents′characteristics, experiences with OTC drugs and attitudes towards the amount of OTC drugs′information from a healthcare professional′s perspective. Twenty-nine hospital pharmacists and 30 community pharmacists responded. Sixty-nine percent of the hospital pharmacists and 50.0% of the community pharmacists thought the amount of information on the package inserts was “adequate”. While a third of each group cumulatively responded with “inadequate” and indicated the need for more information on the points such as drug interactions, pharmacokinetics, details of side effects, and contra-indications. Moreover, more than 50% of each of these groups responded with difficulty in obtaining more detailed information on OTC’s. The study revealed that while the information on the package inserts of OTC’s was adequate for most pharmacists, a significant number desired more detailed information on some points in the package to provide better guidance and healthcare advice to patients.

Pharmaceuticals and Medical Devices Agency (PMDA) has assessed drug safety primarily based on the traditional information such as spontaneous adverse drug reaction reports and post-marketing surveillance results. To overcome the limitation on this approach and to strengthen post-marketing drug safety measures, many efforts has been taken in PMDA in the past several years and are described in this article. Launched in 2009 by PMDA, MIHARI Project-Medical Information for Risk Assessment Initiative aims to establish a new framework for pharmacoepidemiological drug safety assessments utilizing electronic healthcare databases. In this project, many pilot studies have been conducted to characterize the databases including claims data, hospital information system data and Diagnosis Procedure Combination data. Based on many findings and experiences from the pilot studies, a new framework for drug safety assessments was formally implemented in 2014. In 2011, another project called as “MID-NET^®” was launched to develop a new system to actively analyze diverse electronic healthcare data from multiple hospitals in Japan for post-marketing drug safety measures. Studies on data quality and analytical validations including various pilot studies are currently conducted toward full-scale operation of MID-NET^® in 2018. PMDA will continue our challenges to promote public health through these activities.

The Risk Management Plan (RMP) is a document which is shown the consistent risk management of drug from the development phase to the post-marketing phase. RMP mainly consists of safety specifications, pharmacovigilance plans and risk minimization plans. The guidance for RMP was implemented on April 1, 2013. About 3 years have been passed since RMP preparation started to be required, our experience of RMP evaluation is being accumulated. In this paper, we introduce RMP outlines and current status of RMP evaluation in Pharmaceuticals and Medical Devices Agency based on our experience of the RMP review process. Also, we discuss the future directions of RMP, including the promotion of healthcare professionals’ awareness and active use of RMP.

Risk management for pharmaceuticals in post-marketing stage is receiving increasing attention both internationally and domestically. This paper briefly looks back the past situation of pharmacovigilance in Japan and overviews the features and utilization of spontaneous report databases as well as medical databases for pharmacovigilance activities of which environment for practical use has been improved during recent years. Also, the importance of evaluating effectiveness of risk minimization activities is pointed out. Diversification of measures of collecting post-market safety information including the use of different databases is critical. Fundamental knowledge and accumulation of experience of pharmacoepidemiology should be an important basis for the future.

It has been 2 years since Japan also established a system for preparing, submitting, and publishing a risk management plan (RMP) when applying for drug approval. If an RMP functions as it should, even a hypothetical substance that is “very effective, but with a very high risk of adverse reactions” should theoretically have a greater chance of becoming a drug that helps patients to fight disease. In other words, the risk minimization plan in the RMP could successfully minimize the occurrence of serious adverse reactions, while implementation of a risk monitoring plan could aid the timely and accurate detection of new findings unknown at approval. These findings would be included in the risk minimization plan, enhancing it further. However, because it has only been to 2-3 years since RMPs were introduced in Japan, there is still a long way to go before this kind of ideal scenario is realized. Introduction of a pharmacoepidemiologic perspective may be an important factor in making improvements. A sincere effort toward learning this approach will enable the industry to make even more contributions to healthcare and patient’s lives.

Three years have passed since the Japan Risk Management Plan (J-RMP) has been introduced. The current status and the challenges have been reviewed based on the experiences obtained through the activities of the Clinical Evaluation Committee of the Japan Pharmaceutical Manufacturers Association. Several proposals to reach the ideal situation have been made in terms of 1) the identification of the safety specifications, 2) the review process and 3) the additional pharmacovigilance plans. It was revealed that there is a considerable gap between the PMDA’s and the industries’ point of view for all of the three items. From now, the J-RMPs should be developed focusing most of stakeholder’s attention on how safety profile of the medicinal products adequately evaluated in order to maintain the preferable benefit/risk balance of the products throughout their lifecycle.

It is important to overcome a problem of species difference in non-clinical testing during drug development. Human induced pluripotent stem (iPS) cells are expected to resolve the problem. Recently, application of iPS cell-derived cardiomyocytes (iPS-CMs) has been focused on a novel assay system for safety pharmacology. We have prepared a common protocol using iPS-CMs and multi electrode array (MEA) system. From our results of prevalidation study, we organized a nation-wide consortium Japan iPS Cardiac Safety Assessment (JiCSA), for large-scale validation study. JiCSA has improved a MEA-based protocol using iPS-CMs and is now evaluating the effects of 60 compounds using iCell (Cellular Dynamics International) and MED64 MEA system (alpha MED Scientific). In parallel with our prevalidation study, a new CiPA (Comprehensive in vitro Proarrhythmia Assay) paradigm has been proposed by the US Food and Drug Administration (FDA), Cardiac Safety Research Consortium, nonprofit ILSI-Health and Environmental Sciences Institute (HESI), and Safety Pharmacology Society (SPS) for the cardiac proarrhythmia safety. We have shared our protocol and pilot study data using several ion channel blockers with CiPA. Thus, we will collaborate toward establishment of new testing methods to assess the cardiac safety paradigm. This international collaboration will provide scientific basis for revision of ICH S7B guideline. In this review, we will summarize our activities for the development of the standardized protocol using iPS-CMs for safety assessment. This study was supported by grants from the Ministry of Health Labor and Welfare and Japan Agency for Medical Research and development.