Cumulative Adverse Event Reporting of Anaphylaxis After mRNA COVID-19 Vaccine (Pfizer-BioNTech) Injections in Japan: The First-Month Report.

INTRODUCTION: In mid-February, the nationwide immunization plan for the prevention of coronavirus disease 2019 (COVID-19) started in Japan (at first primarily focused on health professionals) using an mRNA-based vaccine (Pfizer/BioNTech). During the phase-in period from February to March, attention was focused on post-vaccination anaphylaxis and anaphylactoid symptoms from the viewpoint of ensuring the safety of the vaccination program. OBJECTIVE: The aim of this report was to provide an update on the status of anaphylaxis and anaphylactoid symptoms occurring after vaccination for COVID-19, as reported under the Adverse Event Following Immunization (AEFI) reporting system in Japan. METHODS: The Pharmaceutical and Medical Devices Agency (PMDA) received AEFI reports from health professionals and manufacturers under the reporting system for AEFI after vaccination for COVID-19, which has been in operation since mid-February 2021. Reported AEFIs of anaphylaxis and anaphylactoid symptoms were assessed using the Brighton Collaboration Criteria to assess diagnostic certainty. RESULTS: 1-month since Japan started the vaccination program for COVID-19 in February 2021, 578,835 doses have been administered to health professionals, with the PMDA receiving 181 suspected event reports of anaphylaxis and anaphylactoid symptoms. In 171 of these 181 cases, women developed these symptoms. Among 181 cases evaluated according to the Brighton Collaboration Criteria, 47 cases (26%) were classified as level 1-3 (reporting rate: 8.1/100,000 doses). CONCLUSION: The results appear similar to reported AEFIs in foreign studies of coronavirus vaccine administration to health professionals, although the reporting rate was higher. Further work is needed to examine the causal relationship of anaphylaxis reactions to coronavirus vaccine administration. Issues of multiple reporting and possible sex/age bias also remain to be analyzed.

PMDA's Vision for Horizon Scanning of Emerging Technologies Potentially Relevant to the Development of New Medical Products: The Regulatory Challenge.

A key goal of regulatory agencies for medical products is to make innovative products available to patients and the medical community in a timely manner in order to improve the quality of public health and health care. Thus, regulators must respond quickly to emerging technologies. It is a horizon scanning method, based on which the Japanese regulatory agency will have the expertise prior to review of forthcoming products of evolving technologies.

Adverse Drug Reaction Relief System in Japan: From Clinical Perspective.

Adverse drug reaction (ADR) relief system in Japan is comprehensively described in this article. Particularly, review process during ADR relief evaluation is focused from clinical perspective. The significance of clinical review process and roles of a physician medical reviewer in the ADR relief system in Japan are also discussed. The current ADR Relief Service in Japan requires criteria for compensation eligibility including the "proper" use of the medication associated with the adverse event, and reasonably plausible association between the drug and the adverse event. The criteria are primarily reviewed at the ADR relief department of Pharmaceuticals and Medical Devices Agency (PMDA). In this article, after introducing framework of the ADR relief system in Japan including review processes at PMDA, actual process of the ADR relief assessment is described. In more details, we explain appropriate indication and appropriate usage in the ADR relief evaluation and unexpected/unwritten ADR in the Japanese package insert. Also described are time period for the payment, causality assessment between ADRs and the death, and pitfalls during the evaluation of the ADR relief system in Japan. In the last part, current issues and future directions are referred.

Evolving Vision of Regulatory Science in the Global Medical Community.

"Regulatory science" (RS) has been defined in various ways, but, nevertheless, the definitions of RS in different parts of the world include many common elements. It seems to be a common view that RS is not basic or applied science but, rather, focuses on the estimation and prediction of safety and efficacy. Thus, we think RS overall should incorporate not only RS specifically for medical product assessment but also RS engineering to provide prediction and estimation tools for those purposes, including guideline/guidance development. It is important as well to consider the potential contribution of RS to rational medicine (i.e., to evidence-based medicine in a broader context), and especially to real-world evidence generation. We will look at how definitions of RS have evolved, and how we believe RS might develop in the future. Taking a patient-centric view, we re-emphasize RS is an ethical science contributing to society and human welfare.

Oseltamivir phosphate-Lifting the restriction on its use to treat teenagers with influenza in Japan.

PURPOSE: In 2007, Ministry of Health, Labour and Welfare (MHLW) warned to refrain from prescribing oseltamivir for teenagers when two Japanese teenagers with influenza fell from a high-rise building after taking oseltamivir. Revisions of the warning texts of anti-influenza drugs were discussed by the Subcommittee of Pharmaceutical Affairs and Food Sanitation Council, MHLW, based on the studies and trends of anti-influenza medication over the last 10 years. METHOD: The research group led by Dr Nobuhiko Okabe conducted nationwide survey since the 2007/2008 influenza season. The results of Japanese and foreign epidemiological and non-clinical studies of abnormal behaviors in influenza patients since 2009 were reviewed. RESULT: Severe abnormal behaviors have been reported in influenza patients taking all types of anti-influenza drugs, as well as in untreated patients. There are some risks to patients whether treated with any anti-influenza drug, or non-treated though it is still not possible to rule out a potential causal relationship between abnormal behaviors and anti-influenza drugs. 70% of abnormal behaviors occurred within two days after the onset of fever. No difference was found between anti-influenza drugs treated and non-treated patients. In patients receiving oseltamivir and other anti-influenza drugs, the frequency of abnormal behaviors is not clearly different between teenagers and patients under 10 years old. CONCLUSION: The specific "boxed warning" and the restriction only for oseltamivir that should not be used for teenagers was lifted. Therefore, the labeling of all anti-influenza drugs carry a consistent warning about the potential for abnormal behaviors in Japan.

New Regulatory Framework for Medical Devices in Japan: Current Regulatory Considerations Regarding Clinical Studies.

In Japan, a recent issue that required an urgent response was the streamlining of regulations concerning clinical trials of medical devices. On July 31, 2017, the Ministry of Health, Labour and Welfare enacted a new regulatory framework called the fast-break scheme for innovative medical devices aiming to expedite patient access while reducing the premarket regulatory burden of clinical trials and enhancing postmarketing commitments. The new framework is expected to provide greater benefits to patients who require access to new medical devices and to companies via improved transparency and predictability, as well as to reduce the social and medical cost incurred for medical innovation.

Report of the International Regulatory Forum on Human Cell Therapy and Gene Therapy Products.

The development of human cell therapy and gene therapy products has progressed internationally. Efforts have been made to address regulatory challenges in the evaluation of quality, efficacy, and safety of the products. In this forum, updates on the specific challenges in quality, efficacy, and safety of products in the view of international development were shared through the exchange of information and opinions among experts from regulatory authorities, academic institutions, and industry practitioners. Sessions identified specific/critical points to consider for the evaluation of human cell therapy and gene therapy products that are different from conventional biological products; common approaches and practices among regulatory regions were also shared. Certain elements of current international guidelines might not be appropriate to be applied to these products. Further, international discussion on the concept of potency and in vivo tumorigenicity studies, among others, is needed. This forum concluded that the continued collective actions are expected to promote international convergence of regulatory approaches of the products. The Pharmaceuticals and Medical Devices Agency and Japanese Society for Regenerative Medicine jointly convened the forum with support from the National Institutes of Biomedical Innovation, Health and Nutrition. Participants at the forum include 300 experts in and outside of Japan.

Response to Nature's editorial regarding the Japanese legal system for regenerative medicines.

Nature's editorial, dated 10 December 2015, made several criticisms of the new Japanese conditional and time-limited marketing authorization system for regenerative medical products. We believe these comments were based on a misunderstanding of the purpose of the regulations, which are patient-oriented, offering patients access to promising regenerative medicines in a timely manner at reasonable expense while also ensuring the efficacy and safety of the medicines. The new regulatory system represents an attempt by Japan to accommodate unmet medical needs, particularly for life-threatening diseases, and is in line with current global regulatory trends to enable early patient access to new therapies.

Regulatory Frameworks for Gene and Cell Therapies in Japan.

The regulations for the human use of advanced therapy medical products such as gene and cell therapy products have evolved in accordance with advance of clinical experience, scientific knowledge, and social acceptance to these technologies. In Japan, two laws, the Pharmaceuticals and Medical Devices (PMD) Act and the Act on the Safety of Regenerative Medicine (ASRM), were enacted in November 2014. The PMD Act defines regenerative medical products for the first time and introduces a system for the conditional and time-limited marketing authorization of regenerative medical products. Under ASRM, the responsibilities of medical institutions to ensure the safety and provide transparency of such medical technologies are described. Amendments to accompanying guidelines for these two Acts are currently in preparation. It is expected that the new legislative frameworks will promote the timely development of new products and technologies, to bring safe and effective regenerative medicines to Japanese patients.

Report of the international conference on regulatory endeavors towards the sound development of human cell therapy products.

The regulation of human cell therapy products is a key factor in their development and use to treat human diseases. In that regard, there is a recognized need for a global effort to develop a set of common principles that may serve to facilitate a convergence of regulatory approaches to ensure the smooth and efficient evaluation of products. This conference, with experts from regulatory agencies, industry, and academia, contributed to the process of developing such a document. Elements that could form a minimum consensus package of requirements for evaluating human cell therapy products were the overall focus of the conference. The important regulatory considerations that are unique to human cell therapy products were highlighted. Sessions addressed specific points that are different from those of traditional biological/biotechnological protein products. Panel discussions complemented the presentations. The conference concluded that most of the current regulatory framework is appropriate for cell therapy, but there are some areas where the application of the requirements for traditional biologicals is inappropriate. In addition, it was agreed that there is a need for international consensus on core regulatory elements, and that one of the major international organizations should take the lead in formulating such a consensus document.

New Japanese initiatives on stem cell therapies.

Two laws aiming to provide a new legal framework to promote regenerative medicine, while ensuring the efficacy and safety of the treatments, came into effect in Japan on November 25, 2014. The scope of these laws is briefly described here.

[Counterfeit medicines--Japan and the world].

Circulating counterfeit medicines in the market is a public health threat. Counterfeit medicines become common problem, not only in developing countries, but also in industrialised countries, as internet has made them more accessible. In Japan, the recent survey on the medicines purchased through on-line pharmacy (targeting Japanese consumers) showed that the majority of erectile dysfunction (ED) medicines imported by individuals in Japan were counterfeit version. The survey of Japanese consumers, who privately imported medicines through on-line pharmacy, indicated that 16% of these consumers experienced adverse events associated with these products. Not only that it is just fake brand, but fake medicines may even cause health hazard. The counterfeit version of Avastin recently detected in the United States became a serious threat for those who desperately need these medicines for life-threatening disease. The Japanese regulatory authorities have provided risk information of counterfeit medicines to general public, as well as monitored on-line pharmacies and conducted enforcement action where necessary. However, more resources of compliance activity should be allocated to respond to the situation of growing threats of counterfeit medicines. Purchasing medicines from abroad through unauthorised channel is the major source of counterfeit medicines. It is essential to prevent circulation of counterfeit medicines through international collaboration of various regulatory authorities. To address these problems, the World Health Organization (WHO) has launched a new Member States Mechanism (MSM) to build network of the authorities. Also, INTERPOL (ICPO) initiated globally concerted enforcement actions (Operation Pangea) against pharmaceutical crime as well as built partnership with pharmaceutical industry to create Pharmaceutical Crime Programme. It is also necessary to prevent consumers encountering counterfeit medicines and to prevent health hazard. The Ministry of Health, Labour and Welfare (MHLW) has been actively involved in prevention and educational activities such as public awareness campaign. MHLW started anti-counterfeit medicines and new psychoactive substance project from February 2013, which centrally collects information about counterfeit medicines, in particular, and provides the risk information more effectively to the public. Japanese Government will work together with international community and contribute to combating counterfeiting through public and private partnership.

Heavy metal contamination of coastal lagoon sediments: Fongafale Islet, Funafuti Atoll, Tuvalu.

To evaluate contamination of coastal sediments along Fongafale Islet, Central Pacific, a field survey was conducted in densely populated, sparsely populated, open dumping and undisturbed natural areas. Current measurements in shallow water of the lagoon indicated that contaminants from the densely populated area would only be transported for a small proportion of a tidal cycle. Acid-volatile sulfides were detected in both the intertidal beach and nearshore zones of the densely populated area, whereas these were no detection in the other areas. This observation lends support to argument that the coastal pollution mechanism that during ebb tide, domestic wastewater leaking from poorly constructed sanitary facilities seeps into the coast. The total concentrations of Cr, Mn, Ni, Cu, Zn, Cd and Pb were relatively high in all of the areas except the undisturbed natural area. The indices of contamination factor, pollution load index and geoaccumulation index were indicative of heavy metal pollution in the three areas. The densely populated area has the most significant contamination; domestic wastewater led to significant contamination of coastal sediments with Cr, Zn, Cu, Pb and Cd. The open dumping area is noteworthy with respect to Mn and Ni, which can be derived from disposed batteries.

New Governmental Regulatory System for Stem Cell-Based Therapies in Japan.

Regenerative medicine using stem cells is expected to provide tools for the replacement or repair of damaged tissues, opening up the possibility of treating many diseases that cannot otherwise be effectively treated. To promote the development of and access to regenerative medicine, it is important to take a balance of expedited provision of innovative therapies and appropriate steps to ensure safety and efficacy. While most developed countries have various regulatory frameworks for clinical trials and medical treatments involving stem cells, the Act on the Safety of Regenerative Medicine and the Revised Pharmaceutical Affairs Law have recently been simultaneously passed by the Japanese Diet. According to the former act, these medical technologies are categorized into 3 classes depending on their anticipated potential risk to human health, and the specific procedures falling into each class are determined. In addition, the act enables medical institutions to commission cell processing by business facilities outside the institution (even foreign facilities) that fulfill the requirements set out by the Ministry of Health, Labour and Welfare, with the aim to promote collaboration between academia and industry from an early stage. According to the latter law, a therapeutic product for regenerative medicine is defined as a product distinct from pharmaceuticals and medical devices, enabling regenerative medical products to be given a conditional, time-limited marketing authorization much earlier than that under the previous system. The new legal framework of regenerative medicine is expected to achieve the aim to develop and promote regenerative medicine, aiming at timely provision of safe and effective therapies and products.

Effects of a sitagliptin safety alert on prescription behaviour for oral antihyperglycaemic drugs: a propensity score-matched cohort study of prescription receipt data in Japan.

BACKGROUND: Sitagliptin, the first of a new class of dipeptidyl peptidase-4 (DPP-4)-inhibitory oral antihyperglycaemic drugs (OHDs), was introduced in Japan in December 2009. In April 2010 a safety alert was issued regarding the risk of serious hypoglycaemic events, and prescribers were recommended to reduce the dose of sulfonylurea (i.e. glimepiride, glibenclamide [glyburide] or gliclazide) in patients receiving a combination of sulfonylurea and sitagliptin. OBJECTIVE: A propensity score-matched cohort study was performed using Japanese pharmacy prescription receipt data for OHDs in order to confirm reported changes in OHD prescription behaviour for patients receiving sitagliptin before and after the safety alert. METHODS: Prescription data from about 6,500 medical institutions throughout Japan during December 2009 to 31 December 2010 were randomly collected from 300 pharmacies, covering 82,064 patients with 629,955 prescriptions for OHDs. Patients who had received a sulfonylurea and sitagliptin (1,788 patients/3,576 prescriptions) before the safety alert were designated as the DPP-4 group. Patients who had received a sulfonylurea but not sitagliptin (30,963 patients/61,926 prescriptions) before the alert were designated as the non-DPP-4 group. Propensity score matching was employed to match baseline characteristics, such as age, sex, type of OHD, metformin use, type of prescribers period for measuring baseline period and type of prescribers' institutions, for 1,783 patients from each group. In the matched cohort, logistic regression analysis was conducted to compare prescription trends before and after the alert. The primary outcome measure of this study was dose of glimepiride, glibenclamide or gliclazide prescribed for DPP-4 and non-DPP-4 patients. RESULTS: In the propensity score-matched cohort, the proportion of glimepiride dose >2 mg of DPP-4 patients was reduced from 45.8 % in Period 1 (before the alert) to 37.5 % in Period 2 (after the alert) (odds ratio [OR] 0.71; 95 % CI 0.579-0.870), whereas in the case of non-DPP-4 patients the proportion was changed from 28.9 % to 29.5 % in the matched cohort (OR 1.03; 95 % CI 0.868-1.215). The mean prescribed glimepiride dose in DPP-4 patients was also reduced from 2.79 ± 1.81 mg in Period 1 (before the alert) to 2.38 ± 1.71 mg in Period 2 (after the alert) [p < 0.0001], whereas the corresponding change in the case of non-DPP-4 patients was from 2.01 ± 1.56 mg to 2.01 ± 1.54 mg (p = 0.94). The difference between the mean prescribed doses in the two groups was statistically significant in both periods. Similar trends of prescription pattern changes were seen for glibenclamide and gliclazide. The reduction of prescribed sulfonylurea dose in DPP-4 patients following the safety alert coincided with a decrease of adverse event reports. CONCLUSION: Our results indicate that propensity score matching to control for baseline characteristics of individual patients and prescribers is a useful approach to avoid selection bias and confounding effects in evaluating the influence of an event on prescription behaviour. This case-matched study indicated that sulfonylurea prescription behaviour changed significantly after the sitagliptin safety alert. There was a significant reduction in sulfonylurea dose after the alert in DPP-4 patients, but not in non-DPP-4 patients. Our findings should be helpful for assessing and improving the effectiveness of other regulatory safety alerts.

Impact of the sitagliptin alert on prescription of oral antihyperglycemic drugs in Japan.

BACKGROUND: Sitagliptin, the first of a new class of dipeptidyl peptidase-4 (DPP-4)-inhibitory oral antihyperglycemic drugs (OHDs), was introduced in Japan in December 2009. In April 2010 a safety alert was issued regarding the risk of serious hypoglycemic events when the drug is used in combination with high-dose sulfonylureas (SUs). OBJECTIVE: To investigate trends in prescription of OHDs before and after the launch of sitagliptin, and before and after the safety alert, in order to evaluate changes in the prescribing behavior of various groups of physicians in response to the safety alert. SETTING: Japan. METHOD: Prescription data from 6,500 institutions, randomly collected from 300 Japanese pharmacies were used. A cohort of 87,678 patients with 813,374 prescriptions for OHDs, among which 464,079 included SUs (glimepiride: 317,423), was collected from August 2009 to 31 December 2010. Logistic regression analysis was conducted. MAIN OUTCOME MEASURE: Prescription trends for sitagliptin and SUs, stratified by age, gender, types of prescribers and institutions. RESULTS: The safety alert recommending a reduction of SU dosing was well reflected in prescriptions issued after the alert (glimepiride dose reduction from 2.78 ± 1.86 mg to 2.32 ± 1.68), especially in prescriptions issued by diabetes specialists (from 2.27 ± 1.81 mg to 1.87 ± 1.47 mg). The dose of background SUs in patients who started sitagliptin early was higher (before alert: 2.70 ± 1.80 mg, after alert: 2.51 ± 1.74 mg) than in patients without experience of sitagliptin (2.12 ± 1.57 mg). This may indicate that patients receiving high-dose SUs were selected for sitagliptin, and this might be a factor in the high frequency of hypoglycemia in the early launch phase of sitagliptin. CONCLUSION: The sitagliptin safety alert had a clear impact on prescribing behavior, but the impact appeared to depend on prescribers' backgrounds. Our findings should be helpful for developing a safer drug launching strategy for new classes of drugs in established categories.