While the need for pediatric drugs has increased in Japan, their development has not been accelerated, resulting in what is called “drug lag” or “drug loss”. As part of our research to identify the causes of the lack of progress in pediatric drug development, we conducted a questionnaire survey of Japanese pharmaceutical companies and drug discovery ventures regarding pediatric drug development. The dominant reasons not to conduct the pediatric drug development were identified as “unprofitable”, “difficulty in conducting clinical studies” and “pediatric indication is not mandatory”. Questionnaires were used to evaluate the current seven systems that could contribute to pediatric drug development. The most common opinion held by 79.1% of companies, was to appreciate the NHI additional fee for pediatric drugs, while all other current systems are affirmed by more than 60% of companies. Fifteen new proposals to extend the benefits of the current system were evaluated. The four proposals for which most respondents (83.6% to 92.5%) voted were “further extension of the maximum patent extension (currently up to 5 years),” “extending the pediatric pricing benefit to adult indications if the drugs are approved for pediatrics,” “extending the reexamination period (exclusivity)” and “promoting acts for disease background research and registries”. Of the questionnaires received, 65.7% had positive opinions (including the opinions that highlighted some issues those need to be resolved) about the introduction of foreign pediatric drug development promotion systems into Japan. However, the survey also identified some problem with our new incentive proposals and the introduction of foreign systems, suggesting that further considerations, including understanding and resolution of these problem, may be necessary for the future pediatric drug development.

Objective: In recent years, with changes in the drug discovery environment, academia-discovered drugs have been the focus of much attention. In this study, we surveyed the characteristics of academia-discovered drugs that have been approved in Japan and/or the United States (US) in the last 20 years to understand the current status and discuss the encouragement of development. Method: This study comprehensively collected information on academia-discovered drugs approved in Japan and/or the US from 2001 to 2020, analyzed their characteristics, and discussed similarities and differences between countries. Result: A total of 73 academia-discovered drugs were approved during the last 20 years, 68 in the US, 47 in Japan and 42 in both countries. Pharmaceuticals with various modalities have been approved continuously, with an increasing number of biologic products in the last five years. These drugs were mainly for therapeutic purposes, and more than 60% received some type of priority review. The initial indications were across a variety of disease areas, but the treatment of “neoplasms” and “endocrine, nutritional or metabolic diseases” was numerous. In this study, that reviewed the academia-discovered drugs approved in Japan and the US, the US accounted for 70% of the academics who have critical patents of the drug and companies responsible for the early clinical development of drugs. There were 17 products approved in the US that were not developed in Japan. Five products were approved only in Japan, but all except Borofalan were developed in the US. Conclusion: In recent years, many academia-discovered drugs for cancer and rare diseases have been approved in Japan and/or the US, and biologic products have increased. To promote academia-discovered drugs in Japan like the US, it is important to invest abundant R & D expenditures, establish a strong R & D ecosystem, and bridge the gap from academia to companies in charge of clinical development.

A new style of clinical trials, called Decentralized Clinical Trials, enables patients to participate in clinical trials with low-frequency visits or without having to visit a site by utilizing new methodologies such as Site to Patient, which entails delivering investigational products (IPs) to a patient from the site and Depot to Patient approach, in which IPs are shipped to the patient’s home directly from the depot without a need for the site. Based on a questionnaire-based survey that we conducted on clinical trial staff with the Academic Research Organization (ARO) Council, we observed the changes in workload associated with the introduction of Depot to Patient and its acceptability, the experience of Site to Patient in clinical trials conducted under the COVID-19 outbreak, and the results of online administration guidance when Site to Patient was conducted. The respondents expected that the introduction of the Depot to Patient approach would reduce their workload, but identified issues such as responsibility and involvement in the selection of vendors as challenges. In addition, even under the COVID-19 outbreak, the experience of Site to Patient was limited, and the staff who had the experience of Site to Patient approach felt an increased workload. Many investigational product administrators answered negatively about the implementation of non-face-to-face drug administration guidance when using Site to Patient approach. Now that the Pharmaceutical and Medical Device Act has been revised to allow online drug administration guidance, it is hoped that the experience and knowledge accumulated will be utilized for non-face-to-face drug administration guidance during Site to Patient or Depot to Patient approach implementation.

While multiple regenerative medical products have been approved in Japan, many changes such as manufacturing process, manufacturing site, analytical procedures, specifications limit, and shelf life can occur through the post-approval lifecycle management. Particularly, cell therapy products using chimeric antigen receptor T cells have characteristics different from ordinary pharmaceutical products, and therefore, are required to take prompt regulatory actions related to changes. When regulatory actions related to changes are taken, notification of minor change or partial change application should be submitted. However, the standard review period for partial change application for regenerative medical products in Japan is 12 months, and it is difficult to say that regulatory actions related to changes can be taken promptly. On the other hand, in 2021, confirmation of a change protocol and a prior notification system for changes in accordance with the protocol (Post-Approval Change Management Protocol: PACMP) were introduced. Based on the protocol agreed with the regulatory authorities, this system allows planned changes to be made promptly upon notification when expected results are obtained. In this study, we investigated whether PACMP can be used to promptly take regulatory actions related to changes in cell therapy products. The results of the investigation showed that, compared with the partial change application, the use of PACMP may enable more rapid changes of about 10-11 months for shelf-life extension and about 4-5 months for addition of manufacturing site and manufacturing process changes. However, it was considered that it would be difficult to change the analytical procedure or specification limit rapidly using PACMP.

Emergency contraceptive pills with levonorgestrel are currently available with a prescription in Japan. Due to public demand, a change in regulations is under consideration. In this paper, we assess the regulations concerning emergency contraceptive pills in Japan and compare them to those of other highly developed countries. Based on this information, we make recommendations on the necessary policy changes and additional measures to implement the switch of emergency contraceptive pills to over-the-counter (non-prescription) status in Japan. In all countries considered in this paper (except for Japan), levonorgestrel emergency contraceptive pills are available without a prescription. We therefore propose levonorgestrel emergency contraceptive pills to be classified as an over-the-counter drug for women over the age of 16, requiring an in-person consultation with the pharmacist. This corresponds to the Japanese classification of“drugs requiring special instruction” (youshidou-iyakuhin). We also propose a change in drug regulations that would allow such drugs to stay within that category. Prices for levonorgestrel emergency contraceptive pills range from free to up to 50 USD in the countries studied; however, in Japan, where the physician’s consultation fee is included, prices can be up to 183 USD. To reduce the financial burden for patients, we therefore recommend the implementation of a policy which would allow patients to have the medication subsidized by health insurance. Furthermore, we propose additional measures pertaining to sex education of the public and pharmacists, updating of pharmacy facilities and cooperation with nearby clinics.

Recent progress in metagenome analysis has offered new insight into pharmacomicrobiomics. For example, the microbiota has been shown to be involved in the intestinal drug metabolism of more than 50 drugs. Although some regulatory points on pharmacomicrobiomics to be considered are mentioned in the guideline for drug-drug interactions（PSEHB/PED Notification No. 0723-4, July 2018）, a series of analyses for current regulatory considerations regarding pharmacomicrobiomics has never been reported. In this study, we reviewed the regulatory points associated with drug metabolism by the microbiota using reports on premarketing evaluations, interview forms, and package inserts of 618 new prescription drugs approved between April 2017 and March 2022. Fifty-five drugs are metabolized, secreted, and reabsorbed via the enterohepatic circulation, and 38 of these drugs are enzymatically converted into glucuronides through glucuronosyltransferases in the liver, possibly allowing them to be excreted in the intestines. Glucuronidases, gut-bacterial enzymes, can deconjugate glucuronides in the intestine, resulting in intestinal absorption of parental drugs. The influence of the microbiota on drug pharmacokinetics is mentioned in the regulatory documents for only 16 drugs. The microbiota compromises approximately 1,000 different microbial species, but in vitro culture systems have never been developed for most of them. The regulatory science for pharmacomicrobiomics continues to be delayed due the lack of effective platforms for studying microbiome-based pharmacokinetics.

Non-conformance with product specifications in stability monitoring, mainly for generic pharmaceuticals, has led to frequent voluntary recalls, suspension of supply, and discontinuation of sales, resulting in large-scale drug shortages in Japan since 2020. We studied the causes and countermeasures of stability-related recalls listed by the Pharmaceuticals and Medical Devices Agency web site and considered these as major risks factors to quality assurance and stable supply. The cases leading to supply suspensions or product discontinuation occurred predominantly among the products of marketing and manufacturing license holders that were subject to administrative action due to Good Manufacturing Practice non-compliance in 2020 and 2021. Many of these products have difficulty ensuring stability even with improved process compliance, strongly suggesting inappropriate formulation and process design that disregards quality by design (QbD) concepts. In addition to improving product development and manufacturing control, revising regulations regarding stability testing conducted during development should reduce stability-associated difficulties. Recalls related to stability monitoring of brand and long-listed formulations occurred mainly for products developed before the 1990s. It should be also necessary to reduce impact of sporadic non-compliance with specifications in the stability monitoring of appropriately developed products on their supply.

MID-NET^® has been in full-scale operation since April 1, 2018, and celebrated its 5th anniversary in April 2023. In this article, we present an overview of MID-NET^® and past activities, as well as describing what has been important in the management of MID-NET^®, research activity for outcome validation, and examples of PMDA’s studies utilizing data from MID-NET^®.

Medical information databases, which systematically accumulate electronic medical information into databases, have been promoted for use in postmarketing safety activities since the environment for their use was partially developing in 2017. The Ministry of Health, Labour, and Welfare (MHLW) issued a notification on the basic approach to using such databases for postmarketing safety surveillance as one of such promotional activities. Full-scale operation of MID-NET^® has started and multiple databases have become available for use for more than 6 years since the issuance of the notification, but such real-world data has remained insufficiently utilized by pharmaceutical companies for their postmarketing safety activities (i. e., enhancement of package insert information, such as precautions for use). Some assert that one of the causes is ambiguity about whether and how evidence obtained from the use of such real-world data can be reflected in package insert material. Under such circumstances, MHLW and Pharmaceuticals and the Medical Devices Agency have recently discussed how to appropriately use the real-world data evidence to enhance package insert information and devised a scheme to practically use the evidence in order to promote the utilization of medical information databases for postmarketing safety measures. Herein, we present the outline of this discussion, along with the related notifications issued in February 2023, as the first-round result of the discussion.

In Japan, Medical Information Database NETwork (MID-NET^®) is a database that collects and analyzes medical information, such as electronic medical records, on a large scale to promote advanced safety measures for pharmaceuticals and other products using medical big data. It is managed and operated by the Pharmaceuticals and Medical Devices Agency. In this study, we examined the problems encountered by each medical institution along with their solutions, focusing on activities related to data standardization and data quality control, which are needed for extensive usage of medical information, including MID-NET^® data. MID-NET^® implemented data quality management since FY2013 as part of preparations for full operation. Data quality management is important for integrated analysis of medical data by multiple institutions, and one of them is standardized code mapping. We developed governance methods for the purpose of improving the medical master quality of cooperating institutions with MID-NET. The proposals of governance results were feedback to each institution, and full operation of the governance was started from August 2020. A tool was developed and automated for the extraction of difference medical master of each institution. Based on the classified results by governance center, the most optimal standardized code was proposed by the medical profession and feedback to each facility monthly. Further studies are needed in order to increase the registration rate after the proposal of standardization code. Standard codes are expected to be more efficient and accurate when managed upstream, such as in the department systems of each institution, rather than managed by each project.

There is a growing need to utilize the Real World Data (RWD) stored in the electronic medical record (EMR) for clinical research and drug development. Since EMR data is managed using local codes in each medical institution, standardization and quality control have become issues. Clinical Research Core Hospitals are working to create the Real World Evidence with the support of AMED. In this effort, Osaka University and Nagoya University are coordinating efforts to standardize EMR data. The goals of this sub-working group are as follows: ① to determine which data items managed in the EMR of each hospital should be converted to standard codes, ② to decide the standard codes to be adopted for each item, the granularity of standardization, and the target range of standardization, ③ to consider the desirable operational flow regarding the person in charge of setting the standard codes and the timing of setting the standard codes, ④ to consider methods to verify that patient data output to SS-MIX2 or data warehouse at each hospital is correctly coded. We are discussing this issue with reference to the preceding MID-NET^® project. In this paper, we introduce our efforts, particularly focusing on standardization, and present the issues that have been identified through these efforts.

Amendment of Good Post-marketing Study Practice in Japan in April 2018 allowed the selection of post-marketing database study as an additional pharmacovigilance activity. Daiichi Sankyo Co., Ltd. started to conduct a post-marketing database study since 2018, and currently conducts 6 studies. Through these results, it was found that some merits of the post-marketing database study compared to the conventional use-results survey were that: 1）It is not required the physicians’ effort to write down case cards 2）It is possible to shorten the time from data acquisition to the initiation of the analysis 3）It is possible to reduce costs and 4）It is possible to mitigate a part of biases in the analysis.

PMDA established Asia Training Center for Pharmaceuticals and Medical Devices Regulatory Affairs (PMDA-ATC) in 2016 which provides trainings for regulators in Asia and around the world. In 2020, against the background of the COVID-19 global pandemic, PMDA-ATC began offering virtual style seminars so called “webinars”. The webinar was the first attempt for PMDA-ATC, but it offers programs that emphasize mutual communication, such as group discussions using case studies in the same manner as previous in-person seminars. In addition, PMDA-ATC started offering video-based E-learning training materials that provide training opportunities to those who are unable to participate the seminars and webinars and are also used as pre- and post- learning of the webinars. There are two types of the E-learning training materials in PMDA-ATC: one is distributed using the YouTube “Pmda Cannel”, which can be viewed by anyone from around the world, and the other is the “PMDA-ATC E-Learning Course”, which is available only to foreign regulators. The contents are not just video of lectures but are designed to be an efficient and effective learning tool. One content is a short video of about 10 minutes, and narration by native English-speakers and PowerPoint animation are inserted. In order to disseminate these PMDA-ATC activities more widely, Facebook and Twitter began disseminating information in June 2022. PMDA-ATC also introduced issuing Digital Certificates for Seminar/Webinar Completion in the form of Open Badges. We would summarize the new initiatives in responses to DX (Digital Transformation) in PMDA-ATC.