Pharmaceuticals And Medical Devices Agency Research Articles

Trend Analysis of Regulatory Approvals for Generics and Biosimilars in Japan: 15 Years of PMDA During Fiscal Years 2009-2023.

Generics and biosimilars play an important role in sustaining the universal healthcare insurance systems in Japan. The Pharmaceuticals and Medical Devices Agency (PMDA) reviews the quality, efficacy, and safety of generics and biosimilars for marketing authorization in Japan. Trend analyses of generics and biosimilars in terms of regulatory science have rarely been published. The PMDA and National Institute of Health Sciences websites were verified for generics and biosimilars, and information related to guidelines and notifications and the number of newly approved generics and biosimilars for fiscal year (FY) 2009-2023 were compiled. Approximately 1,900 and 200 generic drug products were approved in Japan in FY 2010 and 2023, respectively. The number of approved generic drug products has gradually decreased to one-tenth in the past 15years. Overall, 35 biosimilars were approved in FY 2009-2023. The number of approved biosimilars has increased since FY 2017. This article reported a trend analysis of generics and biosimilars in terms of guidelines, notifications, and the number of applied and approved drug products in FY 2009-2023. Our primary goal is to increase patient access to affordable generics and biosimilars with assurance in appropriate quality.

Concordance Between Pharmaceuticals and Medical Devices Agency Review and Ministry of Health, Labour and Welfare Decision Among New Drug Applications in Japan.

New drug applications (NDAs) in Japan are reviewed by the Pharmaceuticals and Medical Devices Agency (PMDA). Those that pass the review are subsequently subject to deliberation by the Ministry of Health, Labour and Welfare Pharmaceutical Affairs and Food Sanitation Councils (MHLW-PAFSC), and the MHLW legislatively grants approval based on its positive opinions. However, little is known regarding the relationship between the PMDA review and the MHLW decision. We retrospectively assessed the MHLW decision of NDAs that passed the PMDA review at the initial MHLW-PAFSC deliberation from 2002 to 2022. The reasoning behind a non-supportive opinion from the MHLW-PAFSC and the sponsor's actions to overcome unresolved issues were also documented. A total of 2,117 of 2,153 (98.3%) NDAs that passed the PMDA review were approved at the initial MHLW-PAFSC deliberation with a positive opinion. The remaining 36 applications were not approved at the initial deliberation and subjected to continued deliberation because of a non-supportive opinion from the councils, although 29 were finally approved through revision of the application document (24 applications), re-analysis of the data (1 application), or additional clinical trials (4 applications). Seven applications have not been approved, of which one was refused, four were withdrawn, and two were unknown. The MHLW approves NDAs that passed the PMDA review at the initial deliberation at a high rate, suggesting that NDAs only suitable for approval passed the review and reached the MHLW-PAFSC deliberation. Only a few NDAs were not approved at the initial deliberation; however, most of them were finally approved.

Has risk management plan system influenced the speed of package insert revisions in Japan?

The system of Risk Management Plan in Japan (J-RMP) is a relatively new system, implemented in 2013; thus, its effect on safety measures is still unclear. One of the purposes of J-RMP is to enhance the postmarketing safety measures to be ensured by publishing J-RMP and sharing information on risk management among healthcare professionals. We hypothesized that this might enable information about postmarketing adverse events to be accumulated rapidly, potentially accelerating the identification of adverse reactions (ARs). Herein, we focused on the speed of adding clinically significant ARs (CSARs) to package inserts (PIs) as an indicator of the rapidity of AR identification, investigated the impact of the J-RMP system on PI revisions. We investigated the "Notice of Revision of Precautions" on the website of Pharmaceuticals and Medical Devices Agency (PMDA), targeting PI revisions with the addition of CSARs from April 2003 to March 2023, which corresponds to 10 years before and after J-RMP implementation in April 2013. We created an original database from public information of PMDA and investigated the speed of adding CSARs to PIs. Comparing the time lapse from drug approvals to PI revisions after J-RMP implementation (149 cases) to that before implementation (318 cases), the median value was 32 months for both. Regarding the time lapse when the additional CSARs were listed and unlisted as safety concerns at the time of approvals, it was 35 months vs. 32 months (14 cases vs. 126 cases, p = 0.7820), with no statistically significant difference. Conversely, there were significant differences within each AR and each drug therapeutic category. This study revealed that the rapidity of risk identification as ARs was not affected by J-RMP, and it may be affected by the characteristics of each AR and each drug therapeutic category. It is expected that other J-RMP benefits, such as risk prevention before the occurrence, will be utilized to further develop strategies for the effective utilization of the J-RMP for safety measures in Japan.

Index of application status transparency and availability of public information for Project Orbis agencies

The purpose of this paper is to provide a guideline for understanding and comparing the regulatory framework of Project Orbis Partners (POPs) and Project Orbis observers, with a focus on their approaches to drug approvals, rejections, and withdrawals. While each agency has its own regulatory framework and guidance, there are some similarities and differences between the language used to describe drug approvals, rejections, withdrawals, and the public availability of these decisions. Project Orbis is an international partnership of regulatory agency, led by the U.S. Food and Drug Administration (FDA), aimed at streamlining the submission and review processes to expedite the global availability of oncology medications for patients. Since its inception, Australia’s Therapeutic Goods Administration (TGA), Brazil’s National Health Surveillance Agency (ANVISA), Canada’s Health Canada (HC), Israel’s Ministry of Health (IMoH) Medical Technologies, Health Information, Innovation and Research (MTIIR) Directorate, Singapore’s Health Sciences Authority (HSA), Switzerland’s Swissmedic (SMC), and United Kingdom’s Medicines and Healthcare Products Regulatory Agency (MHRA) have joined and become POPs. Other international agencies such as, the European Medicines Agency (EMA) and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) are currently observing Project Orbis, as of late 2023. They are not full Project Orbis partners but work closely with the FDA to facilitate oncology drug approval through international collaboration. Running Title: An Index of the FDA and international regulators involved in Project Orbis looking at the similarities and differences between approval, rejection, and withdrawal characteristics of applications and public transparency of actions.

Utility of Biomarker-Informed Drug Interaction Evaluation in Drug Development and Regulatory Decision Making.

The measurement of endogenous biomarkers in plasma and urine before and after administration of an investigational drug in a clinical study may provide an early indication of its drug-drug interaction (DDI) potential via a specific pathway. In the first international harmonized guideline on drug interaction studies, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) M12, endogenous biomarkers have been recognized as an emerging approach in the transporter- and enzyme-based DDI risk assessment. Clinical Pharmacology Roundtable Conference 2024 held at Pharmaceuticals and Medical Devices Agency (PMDA) brought together experts from regulatory agencies, academia, and industries to discuss potential advantages and challenges of the biomarkers approach in drug development and regulatory decision making. This meeting report facilitates stakeholders involved in drug development in better understanding the utility of biomarker approaches and promotes early implementation of biomarker-informed DDI evaluation in regulatory use.

Trends in the market for drug delivery devices categorized as combination drugs and medical devices and regulatory challenges for autoinjectors in Japan.

Although a variety of drug delivery devices have been launched in recent years, few studies have comprehensively investigated the market trends of combination drugs and medical devices approved or certified in Japan and the regulatory challenges related to their approval. Among the drug delivery devices, autoinjectors are more convenient than traditional prefilled syringes and are designed with safety features to prevent needlestick accidents, allowing self-injection by patients. Therefore, autoinjectors have been incorporated into the treatment of various diseases and have shown significant growth among drug delivery devices. This study aimed to investigate the market trends of combination drugs approved in Japan, especially those with autoinjector formulations, and to explore the challenges in the regulatory aspects of combination drugs. Information on the number of marketed drugs and medical devices was obtained from the Pharmaceuticals and Medical Devices Agency (PMDA) database using specific definitions. We looked at the annual changes in the number of drug delivery devices approved and certified as combination drugs or medical devices and the number of canceled certifications. We also examined the classification and main certification criteria for Japanese medical device nomenclature. The study suggested that the number of combination drugs with autoinjector formulations is increasing, replacing previously approved or certified pen-type medication injectors. Moreover, 53% of all drug products were approved for autoinjector formulations after the initial authorization approval in Japan, and more than half of them obtained approval for additional formulations for autoinjectors within five years of the initial authorization approval, with the largest number of cases obtaining approval for additional formulations two years later. The lack of clear regulatory requirements for autoinjectors may lead to confusion among applicants. Furthermore, there are challenges in filing regulatory applications, thus hindering the rapid launch of combination drug-utilizing devices with superior usability.

Continued cancer drug approvals in Japan and Europe after market withdrawal in the United States: A comparative study of accelerated approvals.

Regulatory authorities must balance ensuring evidence of efficacy and safety of new drugs. Various regulatory pathways, such as the accelerated approval program in the United States (US), allow authorities to quickly approve drugs for severely ill patients by granting market authorization based on surrogate end points and pending confirmatory trials. In this cross-sectional study, we considered 23 indications of cancer drugs that received accelerated approval by the US Food and Drug Administration (FDA) but were subsequently withdrawn as of April 2023. Our investigation extended to assessing the regulatory status of these accelerated approvals in the European Union (EU) and Japan, examining relevant regulatory documents and identifying factors contributing to the withdrawal in the United States. Comparing regions, we found that for 52% (12/23) and 30% (7/23) of withdrawn accelerated approvals in the United States, sponsors had also sought marketing authorization from the European Medicines Agency (EMA) and Japan's Pharmaceuticals and Medical Devices Agency (PMDA), respectively. As of the April 30, 2023 study cutoff date, 83% (10/12) of drug-indication pairs remained approved by the EMA, while the PMDA retained 100% (7/7). For these indications, the time from FDA withdrawal until the study cutoff date ranged from 0.23 years to 11.45 years for EMA approvals (median: 1.28 years) and 1.10 years to 11.45 years for PMDA approvals (median: 3.22 years). These findings highlight substantial regulatory discrepancies concerning cancer drugs with unconfirmed benefits. Addressing these discrepancies may involve requiring pharmaceutical companies to confirm clinical benefits using more robust end points and fostering international harmonization in regulators' assessment.

Assessing drug lag in new drug approvals by the Iran Food and Drug Administration compared to the U.S. FDA, EMA, and PMDA: A 20-year analysis (2001-2021).

The pharmaceutical industry is vital for healthcare advancement through innovative medications, improving lives. A substantial challenge is "Drug lag," hindering patient access and increasing disease adjusted life years burdens. We aim to examine drug lag for Iran Food and Drug Administration (IFDA) approved drugs versus US Food & Drug Administration (FDA), European Medicines Agency (EMA), and Pharmaceuticals and Medical Devices Agency (PMDA) over 2001 to 2021. We reviewed new molecular entities within this period, using descriptive statistics in Excel 2019. Drug lag is assessed from relative and absolute perspectives, considering approval gaps and annual rates. Among 710 FDA-approved drugs, 410 received EMA approval, 344 from PMDA, and 148 from IFDA. For 148 IFDA and FDA-approved drugs, the maximum drug lag was 237 months. The mean relative drug lag was 65.18 ± 61.56 months. Compared to EMA (112 drugs), the maximum lag was 257 months, with a mean relative lag of 70.29 ± 53.67 months. With PMDA (127 drugs), the maximum lag was 253 months, with a mean relative lag of 38.23 ± 60.57 months. Iran faces significant drug lag compared to developed countries' regulatory bodies, limiting patient access to innovative treatments. Addressing this issue is crucial for timely drug access, reducing disease burdens. Further research and policy interventions are needed to mitigate drug lag's impact on Iran healthcare landscape.

A retrospective machine learning–based analysis of nationwide cancer comprehensive genomic profiling data to identify features associated with recommendation of mutation-based therapy.

e13510 Background: Comprehensive genomic profiling (CGP) has played key roles in cancer precision medicine through optimization of therapeutic interventions based on genomic alterations in cancer cells. However, the probability of discovering mutation-based treatments through CGP remains low. To enhance the effectiveness and efficiency of cancer precision medicine, it is crucial to identify patients who are likely to benefit from CGP tests. This study aims to identify characteristics of patients in which mutation-based treatments are discovered by CGP tests. Methods: We retrospectively analyzed data from 60,655 patients who underwent CGP tests and were registered in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT), the national data center for cancer CGP in Japan. The C-CAT database covers 99.7% of cancer patients who have undergone CGP tests in Japan. Major cancer types included 10,182 cases of bowel cancer, 8,691 pancreas cancer, 5,062 biliary tract cancer, and 3,777 breast cancer. We developed an eXtreme Gradient Boosting (XGBoost) model using machine learning, and used clinical information as input to predict whether one or more Japanese Pharmaceuticals and Medical Devices Agency (PMDA)-approved drugs are discovered through CGP tests or not. Shapley Additive Explanations (SHAP) was employed to extract significant features that contribute to the model prediction. Results: The prediction model achieved an area under the receiver operating characteristic curve of 0.826 for the overall cancer population. Positive SHAP values were observed for patients with breast (mean SHAP in breast cancer patients: 1.38), lung (1.08), bowel (0.75), and pancreas cancers (0.35), while negative SHAP values were associated with head and neck (-1.75), cervical cancers (-1.54), and brain (-1.33). Positive SHAP values were also associated with presence of liver or lymph node metastasis (0.23, 0.08), shorter intervals between diagnosis and CGP testing or specimen collection and CGP testing, and advanced age. Similar trends were observed in cancer-type-specific prediction models, which also identified their own unique features. In the adolescent and young adult (AYA) age group, primary brain tumors were strongly associated with negative SHAP values (-1.37). Conclusions: Our machine learning-based analysis of nationwide CGP data identified features that predict cases in which mutation-based treatments are discovered by CGP tests, both in the overall cancer population and within specific cancer types and the AYA age group. Expedited CGP testing is recommended for patients who match the identified profile to facilitate early targeted therapy interventions.

Survey of Data Package and Sample Size of Comparative Clinical Studies for Biosimilar Developments from PMDA Assessments.

The Japanese biosimilar guideline requires that the sponsors conduct clinical studies such as comparative pharmacokinetic (PK), pharmacodynamic (PD), or efficacy studies. In each biosimilar development, the sponsors consider the clinical data package, and thus clinical data packages vary among biosimilar developments. The aim of this study was to elucidate the clinical data packages for the biosimilars approved in Japan. The details of clinical data packages and sample size for the regulatory approvals of biosimilars in Japan was reported. We surveyed the clinical data packages and sample size based on the Pharmaceuticals and Medical Devices Agency (PMDA) website review reports between 2009 and 2023. Twenty-four biosimilars have been approved based on the comparative PK and efficacy studies, 10 biosimilars have been approved based on the comparative PK/PD study, and one biosimilar has been approved based on the comparative efficacy study. Regarding the sample size, comparative PK studies were conducted in healthy volunteers or patients for up to 300 cases, although the majority enrolled only 1-100 cases (68.1%, 32/47). Comparative PD studies enrolling 1-30, 31-60, and 61-90 cases totaled 4, 7, and 4 cases, respectively. Finally, comparative efficacy studies enrolling 1-300, 301-600, and 601-900 totaled 6, 10, and 11 cases, respectively. In particular, the oncology and rheumatology areas were the first and second disease areas recruiting 601-900 patients. Large numbers of patients were enrolled to conduct a comparative efficacy study. Efficient biosimilar development should be considered on the basis of the accumulation of scientific understanding of comparable features of biosimilars and their development.

Postmarket safety communications on drugs approved in Japan: A 25-year analysis.

Drug safety communications (DSCs) are essential tools for communicating important postmarket serious drug safety information to healthcare professionals and patients. Previous studies characterized DSCs issued by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA); however, knowledge about the activities of the Pharmaceuticals and Medical Devices Agency (PMDA)/the Ministry of Health, Labor and Welfare (MHLW) is limited. This study characterized DSCs by the PMDA/MHLW in comparison with previously reported DSCs by the FDA and the EMA. We retrospectively analyzed 37 DSCs of 41 adverse drug reactions (ADRs) for 33 drugs in Japan from 1997 to 2022. Most DSCs were related to non-oncology drugs (30/37, 81.1%), and the median (interquartile range) time from approval to DSC issuance was 19 (10-51) months. Notably, the regulatory review reports and the latest labels before DSC issuance did not describe 16/28 (57.1%) and 12/37 (32.4%) of the ADRs related to DSCs, respectively. Most DSCs resulted in label revisions (36/37, 97.3%) and seven drugs were eventually withdrawn. Some DSC characteristics are similar among the PMDA/MHLW, the FDA, and the EMA; however, the number, contents, and range of new safety issues addressed by DSCs differ among the three jurisdictions. Our study emphasized the importance of continuous efforts to gather postmarket drug safety information because substantial ADRs that led to DSCs were recognized after approval and were associated with critical label revisions and withdrawals. Future studies are required to address global challenges for regulatory harmonization of safety-related regulatory actions.

A Sponsor's Perspective on the Contribution of Regulatory-Required Observational Post-Marketing Studies to Understanding Human Drug Product Benefit/Risk in Japan.

Following marketing authorization in Japan, for almost all new drugs or new indications, postmarketing studies (PMS) are a regulatory requirement. These PMS focus on accrual of a defined number of cases with data being collected for a predetermined period after approval to confirm efficacy/effectiveness, safety, and quality in the Japanese population. In contrast to other regions where PMS are only required to address a specific scientific uncertainty, in Japan, PMS are often required regardless of any specific scientific uncertainty, and therefore, their scientific value is unclear. To determine the contribution to the understanding of benefit/risk of PMS conducted by Pfizer in Japan over 2000-2020 for Pharmaceuticals and Medical Devices Agency (PMDA) reexamination. A retrospective analysis of all Pfizer Japan postmarketing studies (PMS) during 2000-2020 was performed. Available Pfizer clinical study reports (CSRs) and PMDA reexamination reports (RERs) were reviewed for key safety findings. The primary analysis was conducted on the subset of PMS that had both an English CSR and a discussion of that PMS in the relevant RER issued by the PMDA, which was subsequently translated into English by a professional translation vendor. Reexamination outcome is included in each RER and served to demonstrate the impact of the study of the benefit/risk profile of the drug. A total of 79 PMS for 43 different drug products across therapy areas enrolled a total of 98,035 patients. The 79 PMS comprised 34 general drug use investigation (GDUI) studies and 45 special investigation (SI) studies. The primary analysis involved 37 PMS with a CSR and RER available in English (40,470 patients); all of which were observational in design. For 31 of 37 PMS, the RER concluded the overall adverse drug reaction (ADR) rate in the PMS was nominally lower than in the phase 3 program. Unlabeled ADRs were reported in 28 of 37 PMS; however, no new safety concerns requiring regulatory action arose from any PMS. The PMDA did not require additional risk minimization measures for any of the 43 drug products studied in any of the 79 PMS assessed. Japan PMS data were consistent with prior global data with no evidence of clinically meaningful differences in safety in Japanese patients. In all cases, the reexamination outcome was category 1 ("usefulness is confirmed"). The reexamination process did not result in regulatory changes for any of the examined drugs. The Japan new-drug application (J-NDA) review and approval process, including implementation of the initial Japan product label, assures acceptable benefit/risk at the time of approval such that mandatory GDUI or SI studies for all products should be reconsidered. In the case of genuine scientific uncertainty to the extent that the benefit/risk of the product is not clear, a PMS is warranted.

Therapeutic applications of carbohydrate-based compounds: a sweet solution for medical advancement.

Carbohydrates, one of the most abundant biomolecules found in nature, have been seen traditionally as a dietary component of foods. Recent findings, however, have unveiledtheir medicinal potential in the form of carbohydrates-derived drugs. Their remarkable structural diversity, high optical purity, bioavailability, low toxicity and the presence of multiple functional groups have positioned them as a valuable scaffold and an exciting frontier in contemporary therapeutics. At present, more than 170 carbohydrates-based therapeutics have been granted approval by varying regulatory agencies such as United States Food and Drug Administration (FDA), Japan Pharmaceuticals and Medical Devices Agency (PMDA), Chinese National Medical Products Administration (NMPA), and the European Medicines Agency (EMA). This article exploresan overview of the fascinating potential and impact of carbohydrate-derived compounds as pharmacological agents and drug delivery vehicles.

Characterization of Chemical Interactions between Clinical Drugs and the Oral Bacterium, Corynebacterium matruchotii, via Bioactivity-HiTES.

In the field of natural product research, the rediscovery of already-known compounds is one of the significant issues hindering new drug development. Recently, an innovative approach called bioactivity-HiTES has been developed to overcome this limitation, and several new bioactive metabolites have been successfully characterized by this method. In this study, we applied bioactivity-HiTES to Corynebacterium matruchotii, the human oral bacterium, with 3120 clinical drugs as potential elicitors. As a result, we identified two cryptic metabolites, methylindole-3-acetate (MIAA) and indole-3-acetic acid (IAA), elicited by imidafenacin, a urinary antispasmodic drug approved by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA). MIAA showed weak antibacterial activity against a pulmonary disease-causing Mycobacterium conceptionense with an IC50 value of 185.7 μM. Unexpectedly, we also found that C. matruchotii metabolized fludarabine phosphate, a USFDA-approved anticancer drug, to 2-fluoroadenine which displayed moderate antibacterial activity against both Bacillus subtilis and Escherichia coli, with IC50 values of 8.9 and 20.1 μM, respectively. Finally, acelarin, a prodrug of the anticancer drug gemcitabine, was found to exhibit unreported antibacterial activity against B. subtilis with an IC50 value of 33.6 μM through the bioactivity-HiTES method as well. These results indicate that bioactivity-HiTES can also be applied to discover biotransformed products in addition to finding cryptic metabolites in microbes.

(139) Efficacy of a New Vacuum Erection Device (Vigor 2020) for Erectile Dysfunction in a Retrospective Study in Japan

Abstract Introduction Phosphodiesterase 5 inhibitors (PDE5i) are the first-line treatment for erectile dysfunction (ED), but there is in approximately 30% of ineffective patients or contraindicated in patients taking nitrate medications. Although vacuum erection device (VED) is the second line in ED guidelines, they have long been unavailable in Japan, due to the withdrawal of their manufacturers. Objective A new VED, Vigor 2020, has now been manufactured and received medical approval by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. It is very important to be able to sexual intercourse with VED, recommended in the ED guidelines. We conducted a retrospective observational study of patients with Vigor 2020 in clinical practice. Methods We analyzed male patients aged 20 years or older who presented to an outpatient clinic with ED and were treated with Vigor 2020 as a second-line treatment, because PDE5i was ineffective or contraindicated. Sexual and ejaculatory function were assessed using questionnaires [Erection Hardness Score (EHS), International Index of Erectile Function (IIEF), Male Sexual Health Questionnaire for assessing ejaculatory dysfunction (MSHQ-EjD), the numerical rating scale (NRS)]. Results There were 34 participants who could be evaluated before and after the use of Vigor 2020, with a mean age of 57.85 (27–86) years. Significant improvement in EHS and IIEF total score were observed with the use of Vigor 2020 in all participants. There was a significant improvement in MSHQ-EjD and NRS for participants who had an EHS of 3 or higher after the use of Vigor 2020. But no significant improvement in MSHQ-EjD and NRS for participants who had an EHS of 2 or lower after the use of Vigor 2020. The participants experienced no significant adverse events. Conclusions Vigor 2020 may be one treatment tool for ED, as defined in the ED guidelines. There is not only significant improvement of erection with Vigor 2020 but also improvement of ejaculation in cases of significant erectile efficacy. Disclosure No.

The Impact of Regulatory Reforms in China on Drug Lag: The Role of Clinical Development Strategies.

In recent years, there has been significant focus on China's new drug lag, but relevant research is limited. This study explores the reasons for drug lag by assessing the impact of reforms in China's drug review system, particularly focusing on the influence of clinical development strategies. This study selected drugs first launched in the United States between 2017 and 2022, examining absolute and relative lag between China and the first-launch country (including submission and review lag). These delays with drugs approved in the European Union and Japan during the same period were compared with uncover the roots of delays in China, further identifying potential factors that could reduce these delays. The results indicate that the National Medical Products Administration (NMPA) has a longer relative lag compared with the European Medicines Agency (EMA) and the Pharmaceuticals and Medical Devices Agency (PMDA). The submission lag time of the NMPA significantly surpasses that of the EMA and PMDA, whereas the review lag time of the NMPA exceeds that of the PMDA but falls short of the EMA. Focusing on clinical trial strategies, bridging trials and multiregional clinical trials (MRCTs) are typically required by the NMPA in East Asia, resulting in longer clinical delay time. Whereas the EMA and PMDA primarily require international MRCTs in Europe and America, with a clinical delay of < 5 months. It is evident that there is a significant gap in clinical trial durations between China and other countries. Further optimization of clinical trial management is necessary to address the lag for new drugs in China.

Induced Pluripotent Stem Cell-Derived Cardiomyocytes: From Regulatory Status to Clinical Translation.

Cardiovascular diseases, considered the deadliest worldwide by the World Health Organization (WHO), lack effective therapies for regenerating cardiomyocytes. With their self-renewal and pluripotency capabilities, stem cell therapies are increasingly used in precision medicine. Induced pluripotent stem cells (iPSCs) are a promising alternative to embryonic stem cells. Good Manufacturing Practice (GMP) principles are not yet adapted for large-scale production of iPSCs. Additionally, the quality risk for iPSC products may not always be possible to eliminate, potentially jeopardizing the health of patients. This review aims to identify critical quality attributes (CQAs) for iPSC-derived cardiomyocytes (iPSC-CMs) for the development of cardiovascular therapy to ensure compliance with regulations and safety for patients. To attain these goals, the literature review was conducted with articles related to iPSCs and iPSC-CM therapies, legislation, and regulatory guidelines of the European Medicines Agency (EMA), Food and Drug Administration (FDA), and Pharmaceuticals and Medical Devices Agency (PMDA). In conclusion, additional regulations and guidelines are needed to monitor differentiation, maturation, and tumorigenicity. GMP-compliant cell banks and fast-track approval systems may increase accessibility for patients.

Current situation and issues regarding termination of risk management plans in Japan.

In Japan, drugs approved after the 2013 implementation of the risk management plan (RMP) have the opportunity to be evaluated for RMP termination. However, the guidelines for risk management following the termination of an RMP remain unclear. Drugs are evaluated for RMP termination at the timing of reexamination. Reexamination system is unique to Japan and initiated in 1979, verifies the approved efficacy and safety of a newly marketed drug based on the data from its actual use over a certain period. This study investigated drugs in Japan for which the RMP requirement was lifted upon reexamination and those for which it was not. We organized their characteristics and considered future issues. We identified drugs with RMPs and obtained information on RMP termination from the public website of the Pharmaceuticals and Medical Devices Agency (PMDA). The survey period spanned 10 years, from April 2013, when the RMP was implemented, to March 2023. During the survey period, 72 drugs with RMPs completed reexamination in Japan. The RMP requirement was lifted for 69 drugs (95.8%) and remained for three drugs (4.2%). Upon RMP termination, 16 out of 69 drugs (23.2%) had important potential risks not listed in the package insert, with malignant neoplasm being the most common. Eleven drugs (15.9%) had important missing information not listed in the package insert, with the most common being the impact on cardiovascular risk. Two drugs (2.9%) had ongoing additional pharmacovigilance activities, and 43 drugs (62.3%) had additional risk minimization activities. Upon reexamination completion, the RMP requirement was lifted for many drugs and remained for a few. Should safety concerns require continued attention following reexamination, we advocate for the continuation of the RMP, guided by more explicit rules. In light of the harmonization of RMP rules with those of other countries, there is a desire for enhanced drug safety management.

Review of COVID-19 Therapeutics by Mechanism: From Discovery to Approval.

The global research and pharmaceutical community rapidly mobilized to develop treatments for coronavirus disease 2019 (COVID-19). Existing treatments have been repurposed and new drugs have emerged. Here we summarize mechanisms and clinical trials of COVID-19 therapeutics approved or in development. Two reviewers, working independently, reviewed published data for approved COVID-19 vaccines and drugs, as well as developmental pipelines, using databases from the following organizations: United States Food and Drug Administration (US-FDA), European Medicines Agency (EMA), Japanese Pharmaceutical and Medical Devices Agency (PMDA), and ClinicalTrials.gov. In all, 387 drugs were found for initial review. After removing unrelated trials and drugs, 66 drugs were selected, including 17 approved drugs and 49 drugs under development. These drugs were classified into six categories: 1) drugs targeting the viral life cycle 2) Anti-severe acute respiratory syndrome coronavirus 2 Monoclonal Antibodies, 3) immunomodulators, 4) anti-coagulants, 5) COVID-19-induced neuropathy drugs, and 6) other therapeutics. Among the 49 drugs under development are the following: 6 drugs targeting the viral life cycle, 12 immunosuppression drugs, 2 immunostimulants, 2 HIF-PHD targeting drugs, 3 GM-CSF targeting drugs, 5 anti-coagulants, 2 COVID-19-induced neuropathy drugs, and 17 others. This review provides insight into mechanisms of action, properties, and indications for COVID-19 medications.

Regulatory Authority in Pharmacovigilance

Abstract: Based on their Gross National Income (GNI) per capita, the World Bank has categorized 80 economies as HighIncome. Global pharmacovigilance rules are primarily driven by three major regulatory stakeholders: the Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency (PMDA). This article's goal is to provide an overview of pharmacovigilance systems and procedures in high-income nations, especially those that are also International Conference on Harmonization (ICH) members. Every high-income nation is a part of the WHO PIDM. Medication safety precautions are directly correlated with a nation's income level. The 10 intrepid members of the Uppsala Monitoring Center are from affluent nations and were among the first to act following the thalidomide catastrophe, establishing drug appraisal committees, launching ADR reporting forms, and implementing safety protocols. Although VigiBase is accessible, several nations have their own databases for data management and analysis, such as the FDA Adverse Event Reporting System, the French pharmacovigilance database, the EU's Eudravigilance system, and Canada's Vigilance online database. Strong pharmacovigilance systems are present in all high-income nations. The two international leaders in pharmacovigilance are the USFDA and EMA. The majority of wealthy nations adhere to EMA regulations. The degree of affluence in a nation directly affects the safety of medicines.