Comparison of the Speed of Enrollment for Clinical Trials Conducted by Japanese and Global Pharmaceutical Companies.

Since the establishment of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), many countries in the world have rapidly improved their clinical trial performance, and the era has come to compare the clinical trial performance of each country. Japan's clinical trials are considered excellent quality, but costly and slow. In this study, we examined the speed of enrollment period in clinical trials. We surveyed clinical trials from January 1, 2010, to December 31, 2019, covering the top 10 pharmaceutical companies in each global sales ranking (Global 10) and the Japanese sales ranking (Japan 10). Clinical trial data were obtained from ClinicalTrials.gov, a clinical trial registration information database, and the speed of participant enrollment (cases/month) was compared for each phase of the trials. The number of clinical trials conducted during the 10 years was 8938 trials for Global 10 and 1439 trials for Japan 10. Comparing the speed of participant enrollment by phase, Japan 10 was significantly faster in phase 1 for both healthy subjects and oncology patients. [Japan 10: Global 10; 15.1 : 12.0 cases/month (healthy subjects) and 5.5 : 1.8 cases/month (oncology), respectively. p < 0.001]. Global 10 was also significantly faster in phase 3. [Japan 10: Global 10; 12.4: 36.9 cases/month, p < 0.001). No significant difference was observed in phase 2 and phase 4. There was a possibility that the speed of enrollment differed by phase between global companies and Japanese domestic companies.

Real-World Predictors of Severe Neutropenia Associated with Palbociclib and Endocrine Therapy for Metastatic Breast Cancer in Japanese Patients.

Therapy for patients of metastatic breast cancer based on palbociclib, a cyclin-dependent kinase 4/6 inhibitor, has been approved in Japan. However, the risk factors for palbociclib-induced severe neutropenia in Japanese patients are rarely reported. Hence, the present study is aimed to identify the risk factors for adverse events requiring palbociclib dose reduction or discontinuation, and to identify the factors necessary to identify a more stable strategy for treatment continuation. This retrospective cohort analysis included patients with advanced breast cancer treated with 125 mg/d palbociclib. We demonstrated that severe neutropenia required significant dose reduction or therapy cessation. Most (77%) of the patients had severe neutropenia within the three courses. Risk factors for grade 3 or higher included low neutrophil counts (< 3250 /µL) before treatment [odds ratio (OR) = 9.10, 95% confidence interval (CI) (2.80-29.41), p < 0.001] and high age-adjusted Charlson comorbidity index (> 9) [OR = 1.64, 95% CI (1.09-2.48), p = 0.018]. Thus, low baseline neutrophil counts and high values for Age-adjusted Charlson comorbidity index are prospective predictive markers for palbociclib-induced severe neutropenia.

A Novel Method for Quantifying Plant Morphological Characteristics Using Normal Vectors and Local Curvature Data via 3D Modelling-A Case Study in Leaf Lettuce.

Three-dimensional measurement is a high-throughput method that can record a large amount of information. Three-dimensional modelling of plants has the possibility to not only automate dimensional measurement, but to also enable visual assessment to be quantified, eliminating ambiguity in human judgment. In this study, we have developed new methods that could be used for the morphological analysis of plants from the information contained in 3D data. Specifically, we investigated characteristics that can be measured by scale (dimension) and/or visual assessment by humans. The latter is particularly novel in this paper. The characteristics that can be measured on a scale-related dimension were tested based on the bounding box, convex hull, column solid, and voxel. Furthermore, for characteristics that can be evaluated by visual assessment, we propose a new method using normal vectors and local curvature (LC) data. For these examinations, we used our highly accurate all-around 3D plant modelling system. The coefficient of determination between manual measurements and the scale-related methods were all above 0.9. Furthermore, the differences in LC calculated from the normal vector data allowed us to visualise and quantify the concavity and convexity of leaves. This technique revealed that there were differences in the time point at which leaf blistering began to develop among the varieties. The precise 3D model made it possible to perform quantitative measurements of lettuce size and morphological characteristics. In addition, the newly proposed LC-based analysis method made it possible to quantify the characteristics that rely on visual assessment. This research paper was able to demonstrate the following possibilities as outcomes: (1) the automation of conventional manual measurements, and (2) the elimination of variability caused by human subjectivity, thereby rendering evaluations by skilled experts unnecessary.

Lag Time for New Innovative, First-in-Class, Drug Approval in Japan.

Early access to novel drugs, regardless of regional differences, is significant for patients worldwide. Although various efforts have been made to reduce the drug lag, it still exists in some regions, including Japan. In this study, we focused on the drug lag of first-in-class drugs in Japan and obtained fundamental information because we considered that first-in-class and me-too drugs are essentially different and should be treated separately. We analyzed 97 first-in-class and 176 me-too drugs in new molecular entity (NME)-approved drugs in Japan and the United States during the fiscal years between 2009 and 2019. Since government policy and the Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs (the Committee) have a huge impact on drug lag, we distinguished NMEs developed at the Committee's request. First-in-class drugs were developed at the Committee's request significantly more than the me-too drugs (p = 0.0034). Although it was not statistically significant, the approval lags were 498.0 d for first-in-class drugs and 535.0 d for me-too drugs. Multiple regression analysis showed that multi-regional clinical trial (MRCT) development strategy (p = 0.0043) and foreign origin drugs (p = 0.0072) were a reducing factor and a prolonging factor of drug lag, respectively. In conclusion, the drug lag for first-in-class drug approval was one year. Global drug development using MRCT is one of the most effective development strategies for reducing drug lags.

Relationships between developmental strategies for additional indications and price revisions for anticancer drugs in Japan.

BACKGROUND: The relationships between developmental strategies for additional indications and drug price revisions have not been thoroughly studied. Here, we investigated the price revisions for anticancer drugs approved in Japan. METHODS: The study was based on published information on anticancer drugs approved between January 2009 and March 2020 in Japan. We investigated the relationships between the pharmacological and regulatory characteristics of anticancer drugs and occurrence/non-occurrence of the Japanese National Health Insurance (NHI) price revisions. RESULTS: Eighty-one new anticancer drugs were given NHI price listings during the survey. On April 1, 2020, the prices of 23 anticancer drugs had been revised from the initial pricing, the prices were reduced for 21 drugs (91.3%). Several parameters showed the relationships between drug characteristics and NHI price revisions. The achievement of additional indications and compound type were identified as explanatory factors for these relationships. Additional indication profiles were defined to assess the relationships between the methods for additional indication achievement and price revisions. When the type of additional indication was "Expansion", the percentage of drugs received NHI price revisions was the highest (P<0.001). CONCLUSIONS: NHI price revision was significantly related to the achievement of additional indications and compound type. The strategy for additional indications was found to affect the occurrence/non-occurrence of NHI price revisions.

TAT-dextran-mediated mitochondrial transfer enhances recovery from models of reperfusion injury in cultured cardiomyocytes.

Acute myocardial infarction is a leading cause of death among single organ diseases. Despite successful reperfusion therapy, ischaemia reperfusion injury (IRI) can induce oxidative stress (OS), cardiomyocyte apoptosis, autophagy and release of inflammatory cytokines, resulting in increased infarct size. In IRI, mitochondrial dysfunction is a key factor, which involves the production of reactive oxygen species, activation of inflammatory signalling cascades or innate immune responses, and apoptosis. Therefore, intercellular mitochondrial transfer could be considered as a promising treatment strategy for ischaemic heart disease. However, low transfer efficiency is a challenge in clinical settings. We previously reported uptake of isolated exogenous mitochondria into cultured cells through co-incubation, mediated by macropinocytosis. Here, we report the use of transactivator of transcription dextran complexes (TAT-dextran) to enhance cellular uptake of exogenous mitochondria and improve the protective effect of mitochondrial replenishment in neonatal rat cardiomyocytes (NRCMs) against OS. TAT-dextran-modified mitochondria (TAT-Mito) showed a significantly higher level of cellular uptake. Mitochondrial transfer into NRCMs resulted in anti-apoptotic capability and prevented the suppression of oxidative phosphorylation in mitochondria after OS. Furthermore, TAT-Mito significantly reduced the apoptotic rates of cardiomyocytes after OS, compared to simple mitochondrial transfer. These results indicate the potential of mitochondrial replenishment therapy in OS-induced myocardial IRI.

Real-time 400 Gbps/carrier WDM transmission over 2,000†km of field-installed G.654.E fiber.

We combine erbium-doped fiber amplifier (EDFA) and backward distributed Raman amplifier (DRA) to achieve the real-time wavelength division multiplexing (WDM) transmission of 400 Gbps/carrier polarization division multiplexing (PDM) 16 quadrature amplitude modulation (QAM) signals over 2,000 km of terrestrial field-deployed cut-off shifted fiber (CSF) compliant with ITU-T G.654.E. This paper compares the transmission performance of 400 Gbps/carrier signals achieved in CSF and standard single-mode fiber (SMF). This transmission distance, 2,019 km, is, to the best of our knowledge, the longest in 400 Gbps/carrier WDM transmission field experiments using digital signal processing (DSP) application specific integrated circuit (ASIC) integrated real-time optical transponders with the technologies to compensate device imperfections; the backward DRA used is fully compliant with laser power safety requirements.

Efficacy and safety of a 3-month dosing regimen of degarelix in Japanese patients with prostate cancer: a phase II maintenance-dose-finding study.

OBJECTIVE: To evaluate the efficacy and safety of degarelix 3-month depot in Japanese patients with prostate cancer. METHODS: In this Phase II, open-label, parallel-group study, 155 Japanese prostate cancer patients were randomized to treatment with degarelix administered subcutaneously at a maintenance dose of 360 or 480 mg every 84 days for 12 months, after receiving an initial dose of 240 mg. The primary endpoint was the cumulative probability of serum testosterone ≤0.5 ng/ml (Days 28-364). Secondary endpoints included percent change in serum prostate-specific antigen level and proportion of patients with prostate-specific antigen failure at Day 364. For safety, adverse events were evaluated. RESULTS: The cumulative probability of serum testosterone ≤0.5 ng/ml (Days 28-364) was 88.3% (95% confidence interval: 77.9-94.0%) and 97.2% (95% confidence interval: 89.4-99.3%) in the 360 and 480 mg groups, respectively. The median percent change in serum prostate-specific antigen level from baseline to Day 364 was -95.05% and -96.43% in the 360 and 480 mg groups, respectively; the proportion of patients with prostate-specific antigen failure was 2.7% and 1.3%. The most frequent adverse event was injection site reaction; however, this did not cause any patient to discontinue treatment. CONCLUSIONS: The 3-month dosing regimen of degarelix 360/480 mg was effective and well tolerated for treatment of Japanese prostate cancer patients. The 480 mg group showed a higher cumulative castration rate than the 360 mg group; thus, 480 mg was considered to be the optimal clinical dosage for future Phase III trials.

A multicenter phase I/II study of enzalutamide in Japanese patients with castration-resistant prostate cancer.

BACKGROUND: The safety, tolerability, pharmacokinetics (PK) and anti-tumor activity of enzalutamide were investigated in patients with castration-resistant prostate cancer (CRPC) in Japan through a multicenter phase I/II study. METHODS: In phase I, patients with progressive metastatic CRPC received single, then multiple, ascending doses of enzalutamide 80, 160 or 240 mg/day. After assessment of tolerability at multiple doses of 160 mg/day for 4 weeks, post-docetaxel patients with CRPC and measurable disease were enrolled into phase II; receiving long-term administration of enzalutamide 160 mg/day. RESULTS: Nine and 38 patients were enrolled in phase I and II, respectively. During phase I, enzalutamide was well tolerated in each cohort; PK parameters were similar to those of non-Japanese populations in other studies. By week 12, overall response rate was 5.3 % and clinical benefit rate was 47.4 %. Prostate-specific antigen response rate (≥50 % reduction from baseline) was 28.9 %. Treatment-emergent adverse events reported in >20 % of patients in phase II were decreased weight, decreased appetite and constipation. No seizures were observed. CONCLUSION: Enzalutamide at 160 mg/day was well tolerated, with PK and safety profiles similar to the non-Japanese population. Anti-tumor activity was observed in post-docetaxel Japanese patients with metastatic CRPC. Apparent differences in anti-tumor activity compared with the AFFIRM study (a phase III trial in a diverse population of patients with CRPC post-docetaxel) may be attributed to differences in treatment history prior to starting enzalutamide. Particularly in Japan, the influence of sequence in hormone treatments, including combined androgen blockade therapy, should be considered. TRIAL REGISTRATION: ClinicalTrials.gov NCT01284920.

Recent trends for drug lag in clinical development of oncology drugs in Japan: does the oncology drug lag still exist in Japan?

BACKGROUND: This study exhaustively and historically investigated the status of drug lag for oncology drugs approved in Japan. METHODS: We comprehensively investigated oncology drugs approved in Japan between April 2001 and July 2014, using publicly available information. We also examined changes in the status of drug lag between Japan and the United States, as well as factors influencing drug lag. RESULTS: This study included 120 applications for approval of oncology drugs in Japan. The median difference over a 13-year period in the approval date between the United States and Japan was 875 days (29.2 months). This figure peaked in 2002, and showed a tendency to decline gradually each year thereafter. In 2014, the median approval lag was 281 days (9.4 months). Multiple regression analysis identified the following potential factors that reduce drug lag: "Japan's participation in global clinical trials"; "bridging strategies"; "designation of priority review in Japan"; and "molecularly targeted drugs". CONCLUSIONS: From 2001 to 2014, molecularly targeted drugs emerged as the predominant oncology drug, and the method of development has changed from full development in Japan or bridging strategy to global simultaneous development by Japan's taking part in global clinical trials. In line with these changes, the drug lag between the United States and Japan has significantly reduced to less than 1 year.

A phase I study of combination therapy with nanoparticle albumin-bound paclitaxel and cyclophosphamide in patients with metastatic or recurrent breast cancer.

BACKGROUND: The objective of the present clinical study is to determine the maximum tolerated dose (MTD)/recommended dose (RD) of combination therapy with nanoparticle albumin-bound paclitaxel (nab-PTX) and cyclophosphamide (CPA) in patients with metastatic or recurrent breast cancer. METHODS: nab-PTX and CPA were administered on the first day of each 21-day treatment cycle. The dose of CPA was fixed at 600 mg/m(2), while the dose of nab-PTX was increased from 180 mg/m(2) (Level 1) to 220 mg/m(2) (Level 2) and then to 260 mg/m(2) (Level 3). RESULTS: A total of 11 patients from two institutions were enrolled in the present study. At Level 3, a dose-limiting toxicity (DLT) was observed in 1 patient. Considering treatment continuity and the risk of adverse events in Cycle 2 and thereafter at this level, further subject enrollment at Level 3 was discontinued after two patients had been enrolled. Since the doses used at Level 3 were considered the MTD of nab-PTX and CPA and the doses used at Level 2 were considered the RD of nab-PTX and CPA, three additional subjects were enrolled at Level 2. No DLTs were observed at Level 2. CONCLUSION: The RD of combination therapy with nab-PTX and CPA was 220 mg/m(2) and 600 mg/m(2), respectively, in patients with metastatic or recurrent breast cancer.

Measurement of maternal cerebral tissue hemoglobin on near-infrared time-resolved spectroscopy in the peripartum period.

AIM: To measure cerebral tissue hemoglobin in uncomplicated and complicated pregnant women during the peripartum period. METHODS: Time-resolved spectroscopy (TRS-20) can measure absolute concentration of oxygenated, deoxygenated, and total tissue hemoglobin based on the transit time of individual photons. Therefore, we used TRS-20 to measured tissue hemoglobin in the hemi-prefrontal lobes of normotensive pregnant women with (n = 51) or without (n = 19) epidural anesthesia, hypertensive pregnant women with pre-eclampsia (n = 10), a pregnant woman with acute onset of hypertension soon after delivery, and a hypertensive woman after hemorrhagic stroke in delivery. RESULTS: Cyclic labor concomitant with intra-abdominal pressure caused synergistic elevation in cerebral tissue hemoglobin. In contrast, epidural anesthesia reduced the amplitude of the cyclic increase of cerebral tissue hemoglobin in normotensive pregnant women. Hypertension in labor due to pre-eclampsia increased the amplitude of synergistic elevation of cerebral tissue hemoglobin caused by cyclic labor and intra-abdominal pressure. A prolonged high basal level of cerebral tissue hemoglobin was observed in a case of acute onset of hypertension soon after delivery. A decrease in cerebral tissue hemoglobin in the hemi-prefrontal lobe was observed in a woman 2 h after the onset of hemorrhagic stroke in labor. CONCLUSIONS: TRS-20 can detect specific changes in maternal cerebral tissue hemoglobin level in response to physiological and pathophysiological changes in delivery. Thus, it represents a promising new conventional tool for maternal cerebral monitoring in the peripartum period.

Differences in maximum tolerated doses and approval doses of molecularly targeted oncology drug between Japan and Western countries.

Approved doses of a number of drugs in Japan are known to be different from those in the United States (US) and the European Union (EU), and doses are often set lower for the Japanese than for the western people. Similarly, some oncology drugs also have lower dose approved for the Japanese than for the western people. A total of 40 oncology drugs were approved as new molecular entities in Japan between 2001 and 2013. Of the 40 drugs, 21 were molecularly targeted drugs and 13 were cytotoxic drugs. Five (12.5 %) of the 40 drugs had different approved dose from that in the US and the EU. Of the 13 cytotoxic drugs, four drugs (30.8 %) differed in approved dose, while all the molecularly targeted drugs (21 of 21 drugs) had the same approved dose. We compared the maximum tolerated dose (MTD) of the 21 molecularly targeted drugs in the Japanese with that in the western people and found that the MTD was determined lower in the Japanese than that in the western people (two drugs), was not different (10 drugs), and MTD was not determined in the Japanese and incommensurable because of the different dose range tested in Japan (nine drugs). All the molecularly targeted drugs are the same in approved doses and few molecularly targeted drugs differ in MTD between Japan and the Western countries.

[Enzalutamide-a novel androgen receptor inhibitor that provides treatment options for patients with castration-resistant prostate cancer].

The recent emergence of new hormonal or chemotherapeutic drugs has resulted in a paradigm shift in the treatment of castration-resistant prostate cancer(CRPC). Enzalutamide is a rationally designed, orally administered androgen receptor(AR)inhibitor. It inhibits multiple points in the androgen receptor signalling pathway, which is considered an important driver of CRPC, including the inhibition of androgen binding to the AR, nuclear translocation of the AR complex, and binding of the AR complex to deoxyribonucleic acid(DNA). Unlike other anti-androgens(such as bicalutamide), enzalutamide does not act as a partial AR agonist. The first in human phase I/II trial was conducted in the United States in both chemotherapy-naïve patients and postchemotherapy patients with progressive metastatic CRPC(mCRPC). The results showed encouraging antitumor activity of enzalutamide by considering all outcomes assessed in the trial. The first reported phase III trial was a randomized, double-blind, placebo-controlled, multinational study involving 1,199 patients with mCRPC that progressed even after docetaxel therapy(AFFIRM trial). Enzalutamide was associated with significant benefits over the placebo considering time-to-event outcomes(i.e. prolonged overall survival[OS], delayed time to prostatic specific antigen[PSA]progression[TTPP], prolonged radiographic progression free survival[rPFS], time to the first skeletal related event[SRE])as well as objective response outcomes(i.e. PSA, soft tissue, and quality of life[QOL]). On the basis of the AFFIRM results, Astellas and Medivation filed a new drug application with the United States Food and Drug Administration and the European Medicines Agency in 2012, and obtained their approval. Another phaseI/II enzalutamide trial was conducted in both chemotherapy-naïve patients and post-chemotherapy pa- tients with progressive mCRPC. Enzalutamide at a dose of 160mg/day was well tolerated, and it showed pharmacokinetic characteristics, adverse events, and anti-tumor activity profiles similar to that of the non-Japanese population. On the basis of the results of the studies summarized above, a new drug application was submitted to the Ministry of Health, Labour, and Welfare of Japan in May 2013 and obtained the approval in Mar 2014. The second phase III trial was a randomized, double-blind, placebo-controlled, multinational study of 1,717 chemotherapy- naïve patients with CRPC(PREVAIL trial). An interim analysis recently demonstrated the significant benefits of enzalutamide over the placebo considering both OS and rPFS. In light of these results, the Independent Data Monitoring Committee (IDMC)advised terminating the study early, and suggested treating the patients in the placebo group with enzalutamide. This paper reviews the developmental history of enzalutamide, its pharmacokinetic and pharmacodynamic characteristics, as well as available efficacy and tolerability data yielded in clinical trials of patients with CRPC.

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

Background: 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. Aim: 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. Methods: 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. Results: 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. Conclusion: 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.

Adult and pediatric relapsing multiple sclerosis phase II and phase III trial design and their primary end points: A systematic review.

No systematic review of trial designs in patients with relapsing multiple sclerosis (RMS) was reported. This systematic review was conducted on the trial designs and primary end points (PEs) of phase II and III trials intended to modify the natural course of the disease in patients with RMS. The purpose of the study is to explore trends/topics and discussion points in clinical trial design and PE, comparing them to regulatory guidelines and expert recommendations. Three trial registration systems, ClinicalTrials.gov, the EU Clinical Trials Register, and the Japan Registry of Clinical Trials, were used and 60 trials were evaluated. The dominant clinical trial design was a randomized controlled parallel-arms trial and other details were as follows: in adult phase III confirmatory trials (n = 32), active-controlled double-blind trial (DBT) (53%) and active-controlled open-label assessor-masking trial (16%); in adult phase II dose-finding trials (n = 9), placebo- and active-controlled DBT (44%), placebo-controlled DBT (22%), and placebo-controlled add-on DBT (22%); and in pediatric phase III confirmatory trials (n = 8), active-controlled DBT (38%) and active-controlled open-label non-masking trial (25%). The most common PEs were as follows: in adult confirmatory trials, annual relapse rate (ARR) (56%) and no evidence of disease activity-3 (NEDA-3) (13%); in adult dose-finding trials, the cumulative number of T1 gadolinium-enhancing lesions (56%), combined unique active lesions (22%), and overall disability response score (22%); and in pediatric confirmatory trials, ARR (38%) and time to first relapse (25%). It was suggested that some parts of the regulatory guidelines and expert recommendations need to be revised.

Comparison of regulatory approval system for medicines in emergency among Japan, the United States, the United Kingdom, Europe, and China.

The approval of pharmaceuticals in response to the COVID-19 pandemic is a global concern, and during emergencies, emergency approval or authorization systems that enable the rapid use of unapproved drugs to maintain national health are essential. However, there is limited research comparing these systems across countries and their effects. This cross-sectional study examined such systems in Japan (JP), Europe (EU), the United Kingdom (UK), and China (CN) for pharmaceuticals (n = 23) authorized under Emergency Use Authorization (EUA) in the United States (US) between December 2019 to July 2023. As of the end of July 2023, JP had granted approval or permission for 14 drugs (60.9%), EU for 14 (60.9%), UK for 12 (52.2%), and CN for three (13.0%). An examination of the developmental status of the 23 drugs revealed that JP had 6 drugs (26.1%), the EU had 3 drugs (8.7%), the UK had 5 drugs (21.7%), and CN had 16 drugs (69.6%) yet to be developed. The US had significantly more granted permissions and developed drugs, while CN the least. The UK had a significantly shorter period for approval than the US and the shortest overall. The EU had the shortest period from the issuance of EUA to approval dates. Although not statistically significant, JP had the longest duration until unapproved drugs could be used. Pharmaceuticals granted usage permission under the EUA in JP, the EU, and the UK were developed or on the market in over 70% of cases, whereas in CN, more than two-thirds were yet to be developed. This suggests that CN may not actively utilize pharmaceuticals from other countries for COVID-19 treatment and may rely on its own. When comparing the emergency approval and permission systems of each country, the most significant difference was in the type of system granting approval.

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

Introduction: 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. Methods: 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. Results: 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. Conclusion: 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.

A Qualitative Interview Study on Expanded Access Clinical Trials for Compassionate Use in Japan.

Purpose: An expanded access clinical trials (EACTs) provides exceptional patient access to investigational new drugs for life-threatening diseases for which no effective treatment exists. Based on public information, we have studied EACTs since 2016, when the EACT system was launched in Japan. In this study, we investigated the reality of EACTs by interviewing pharmaceutical companies and clarifying how they view them. Patients and Methods: We conducted semi-structured interviews with 10 pharmaceutical companies developing new drugs. This study aims to clarify the status of EACTs, so we selected pharmaceutical companies that develop innovative drugs for which they may perform EACTs (however, experience in conducting EACTs was optional). Results: All those surveyed were aware of EACTs. Twelve access clinical trials were conducted, and the EACT implementation rate for pivotal clinical trials was 2.5%. The most common reason for implementing an EACT was "requests from physicians and medical institutions" (nine companies, 90.0%), and the most common reason for not implementing an EACT was "the applicability of the system" (five companies). Improvements to EACTs were identified by eight companies (80.0%); financial assistance by six companies (60.0%); reducing the scope of data to be collected and simplifying the procedure by six companies (60.0%). Seven companies (70.0%) responded that a Single Patient Investigational New Drug Application should be conducted, suggesting that the system should be revised. Conclusion: An interview survey of ten pharmaceutical companies developing new drugs in Japan regarding expanded access clinical trials indicated that there were issues with the system. Many wished to improve the system by establishing a single patient access system, supporting resources, and simplifying procedures. Based on our interviews with 10 Japanese pharmaceutical companies, it was found that the system needed to be improved by introducing a single patient access system, providing supporting resources, and simplifying procedures. In Japan, about eight years have passed since EACT was established, and it appears a revision of the EACT legislation is due.