Japanese Drug Research Articles

Evaluating the Effectiveness of Repricing for Market Expansion in the Japanese Drug Pricing System.

In 1994, the "Repricing for Market Expansion" system (the repricing system) was introduced to the pharmaceutical market in Japan to improve the financial performance of the national health insurance system. In 2010, the "Reward Premiums for the Promotion of Innovative Drug Discovery and the Resolution of Off-Label Use Issue, Etc." system (the reward system) was introduced to promote the development of new drugs. This study evaluates the effectiveness of these systems from an empirical perspective. The data set used in this study was created using publicly available information from the Ministry of Health, Labour and Welfare (MHLW) website and a market database maintained by IMS Japan Pharmaceutical Market Sales. Anticancer or immunomodulating drugs were the most frequently affected by the repricing system. The sales of similar drugs did not exceed double the sales forecast, and to begin with, the repricing system was not applied to these drugs, unintentionally reducing the profitability of pharmaceutical companies. In addition, we found that pharmaceutical expenditures have been steadily and significantly increasing, although this aspect is just one of the circumstances surrounding the Japanese pharmaceutical market. On the basis of these results, we propose that the current repricing system be replaced with one using a market mechanism that can evaluate the value of drugs from an economic perspective and help improving the financial performance of the national health insurance system. We also suggest that the number of generic medications on the market in Japan be increased to a ratio equivalent to those of the US and EU. We hope that the perspectives on Japan's unique drug pricing system obtained from this article are utilized by pharmaceutical companies in developing their businesses in Japan.

Review of the ENCHANTED Trial (Enhanced Control of Hypertension and Thrombolysis Stroke Study): How Low Can We Go With Intravenous Tissue-Type Plasminogen Activator Dose and Blood Pressure Level?

ENCHANTED (Enhanced Control of Hypertensionn and Thrombolysis Stroke Study) was a 2-by-2 quasi-factorial, open-label, noninferiority trial assigning randomly 3310 thrombolysis-eligible patients to low-dose intravenous alteplase (0.6 mg/kg body weight) or to standard dose (0.9 mg per kilogram of body weight). The reported arm of the trial also included 935 patients who were randomly assigned to intensive or guideline-recommended blood pressure management.1 The investigators pointed out that surprisingly little research on the optimal dose of alteplase was conducted compared with cardiovascular studies using thrombolytic therapy and that the standard dose for the NINDS trial (National Institute of Neurological Disorders and Stroke) was chosen on the basis of small pilot dose-escalation studies.2 Furthermore, the Japanese drug authority has approved the lower dose based on an uncontrolled open-label study showing equivalent outcomes and lower frequency of intracerebral hemorrhagic complications compared with the standard dose. Other Asian registry studies showed inconsistent results. However, it would seem that one important aspect driving the idea of the lower dose was affordability of the treatment, and the investigators stated that low-dose alteplase has become a low-cost and possibly safer option for patients who cannot afford the standard dose or are elderly.3 The primary objective of the ENCHANTED trial was to show noninferiority of the low dose compared with the standard one (3-month disability or death, modified Rankin scale score of 2–6). In contrast to equivalence or superiority trials, the noninferiority trials try to show that the tested treatment is not …

Cost-effectiveness of intravitreal aflibercept versus other treatments for wet age-related macular degeneration in Japan

Objective: This analysis estimated the cost-effectiveness of intravitreal aflibercept injection(s) (IAI) for wet age-related macular degeneration (wAMD) compared with other treatments in Japan.Methods: This was a cost-utility analysis based on published data. A state-transition cohort model was constructed with six health states based on best-corrected visual acuity in the better-seeing eye. The cycle time was 4 weeks, and the time horizon was 12 years. The model compared IAI 2 mg every 8 weeks (2q8) for 2 years after three initial monthly injections, ranibizumab as needed, ranibizumab 0.5 mg every 4 weeks (0.5q4), pegaptanib sodium 0.3 mg every 6 weeks, verteporfin photodynamic therapy (PDT), and best supportive care, assumed to include medical management and monitoring, but no active therapy. Costs (expressed as Japanese yen [JPY]) and quality-adjusted life years (QALYs) gained were estimated for each treatment and discounted at 2.0%. Input data were obtained from clinical studies, the Japanese drug tariff and social insurance reimbursement schedule, and expert opinion. The analysis was conducted from the societal perspective, including medical costs as well as costs of blindness.Results: IAI 2q8 was dominant (i.e. more effective in terms of QALYs and less costly) to all other comparators (ranibizumab as needed, ranibizumab 0.5q4, pegaptanib sodium, PDT, and best supportive care), as shown by the incremental cost-utility ratio (i.e. cost per QALY gained).Limitations: The strengths of the analysis include the wide range of comparators evaluated and the use of Japanese-specific utility data. The limitations include the use of one eye, inclusion of published data up to 2 years only, and assumptions on disease course over 5 years.Conclusions: IAI 2q8 was more effective in terms of QALYs and less costly compared with other treatments for wAMD in Japan.

Japan’s generics market challenges foreign API makers

Japan is legendary for its focus—many would say obsession—on producing high-quality products. When it comes to sourcing active pharmaceutical ingredients (APIs), Japanese generic drug firms are equ...

Pharmaceutical Pricing and Reimbursement in Japan: For Faster, More Complete Access to New Drugs.

In Japan, National Health Insurance (NHI) has ensured that all Japanese citizens can use the health services they need for more than 50 years. This paper gives an overview of the Japanese NHI drug price listing scheme and practice, and it also discusses the issue of drug price setting and health insurance system from the viewpoint of better patient access to new drugs as well as the environment for innovative new drug development. For each New Molecular Entity (NME) approved between October 2004 and December 2014, we checked its presence in the list of NHI drug prices as of January 31, 2015, to calculate the NHI coverage rate and the average time between marketing approval and the date of NHI listing. A total of 304 NMEs were listed in the NHI price list during the study period, and the NHI coverage rate (excepting preventive vaccines) was 97.4%. The average time between marketing authorization and the initiation of reimbursement was 66 days. There were 88 drugs that gained premiums for innovativeness/usefulness. From the view of NHI coverage scope and speed, the hurdle to access new drugs in Japan is shown to be lower than in other countries that also set public prices for reimbursement. Although the difficulty of controlling health expenditures increases, drug pricing that properly reflects the drug's clinical value is important in that it also furthers the development of medical technology. Better price setting can also facilitate patient access to innovative drugs.

Japan Pharmacogenomics Data Science Consortium Database and Its Application for Drug Safety Analyses

Severe adverse drug reactions (ADRs) are significantly influenced by the genetic background of an individual, and pharmacogenomics (PGx) is strongly expected to reveal the cause of severe ADRs. Genome-wide association studies (GWASs) for severe ADRs have been conducted worldwide, and a genomic database of representative samples of the ethnic population can be used as controls for GWAS for severe ADRs. Six Japanese pharmaceutical companies, Astellas, Daiichi Sankyo, Mitsubishi Tanabe, Otsuka, Taisho, and Takeda, therefore established the Japan Pharmacogenomics Data Science Consortium (JPDSC) and built a Japanese genomic database in 2009. This database promotes the application of PGx in drug development by each member company and PGx researches for expanding Japanese drug safety information at the genomic level.

HIV-1 CRF01_AE and Subtype B Transmission Networks Crossover: A New AE/B Recombinant Identified in Japan.

The major circulating HIV-1 strains in Japan have been subtype B (B) followed by CRF01_AE (AE) in newly diagnosed HIV/AIDS cases. These two subtypes have distinct epidemiological characteristics; B predominates in men who have sex with men, while AE is observed mostly in heterosexuals engaging in high-risk sex. However, transmission networks of these two high-risk populations appear to be crossing over and diffusing. Here we report the emergence of previously unidentified HIV-1 AE/B recombinants in Japan. We initially identified 13 cases with discordant subtyping results with AE (gag MA)/B (pol PR-RT)/AE (env C2V3) by molecular phylogenetic analysis of 1,070 cases who visited Nagoya Medical Center from 1997 to 2012. Genetic characterization of full-length sequences demonstrated that they shared an identical recombinant structure, and was designated as CRF69_01B by the Los Alamos HIV National Laboratory. By reviewing gag, pol, and env sequences collected in the Japanese Drug Resistance HIV-1 Surveillance Network, we found five other CRF69_01B probable cases from different areas in Japan, suggesting that the strain is transmitted widely throughout the country. The time of the most recent common ancestor analyses estimated that CRF69_01B emerged between 1991 and 1995, soon after AE was introduced from neighboring countries in the mid-1990s. Understanding the current epidemic strains is important for the diagnosis and treatment of HIV/AIDS, as well as for the development of globally effective HIV vaccines.

Polysomnographic Assessment of Sleep Comorbidities in Drug-Naïve Narcolepsy-Spectrum Disorders--A Japanese Cross-Sectional Study.

This is a large cross-sectional study which aimed to investigate comorbidity rate, degree of sleep-related breathing disorder, polysomnigraphically diagnosible rapid eye movement sleep behavior disorder/rapid eye movement sleep without atonia and periodic limb movements during sleep in Japanese drug-naïve patients with narcolepsy-spectrum disorders. A total of 158 consecutive drug naïve patients with narcolepsy with cataplexy, 295 patients with narcolepsy without cataplexy and 395 patients with idiopathic hypersomnia without long sleep time were enrolled. From retrospectively analyzed data of nocturnal polysomnography and multiple sleep latency test, higher rates of periodic limb movements during sleep (> = 15 h-1) (10.2%) and polysomnographically diagnosable rapid eye movement sleep behavior disorder (1.9%) were found in patients with narcolepsy with cataplexy. They had more severe periodic limb movements during sleep especially during rapid eye movement sleep and higher percentages of rapid eye movement sleep without atonia than the other two patient groups. In the present large sample study, Japanese drug naïve patients with narcolepsy with cataplexy showed the highest comorbidity rates of periodic limb movements during sleep, polysomnographically diagnosable rapid eye movement sleep behavior disorder and rapid eye movement sleep without atonia among those with the other narcolepsy-spectrum disorders; the rates were lower than those for Western patients.

Investigation of Gastroduodenal Mucosal Injury in Japanese Asymptomatic Antiplatelet Drug Users.

Antiplatelet drugs are widely used for the prevention of cardiovascular disease and cerebral vascular disorders. Although there have been several studies on gastroduodenal mucosal injury with gastrointestinal (GI) symptoms such as GI bleeding, in antiplatelet drug users (including low-dose aspirin (LDA)), there have been few reports on the association between antiplatelet drug use and gastroduodenal mucosal injury in asymptomatic antiplatelet drug users. This study was a cross-sectional study elucidating the association between antiplatelet drug use and gastroduodenal mucosal injury in asymptomatic antiplatelet drug users.Subjects were 186 asymptomatic Japanese antiplatelet drug users who underwent a regular health checkup. Subjects were divided into those with and without gastroduodenal mucosal injury endoscopically, and the association between gastroduodenal mucosal injury and other data in asymptomatic antiplatelet drug users was investigated.The prevalence of males and drinkers were significantly higher in subjects with gastroduodenal mucosal injury than in those without. In addition, the prevalence of proton pump inhibitor (PPI) users was significantly lower in subjects with gastroduodenal mucosal injury than in subjects without gastroduodenal mucosal injury. Logistic regression analysis showed PPI (odds ratios: 0.116; 95% confidence intervals: 0.021–0.638; P < 0.05) was a significant predictor of a decreased prevalence of gastroduodenal mucosal injury and closed-type (C-type) atrophy (3.172; 1.322–7.609; P < 0.01) was a significant predictor of an increased prevalence of severe gastroduodenal mucosal injury in asymptomatic antiplatelet drug users.Gender and lifestyle, such as drinking, may have an impact on risk of gastroduodenal mucosal injury in asymptomatic subjects taking antiplatelet drugs. Although PPI is a significant predictor of a decreased prevalence of gastroduodenal mucosal injury, including in asymptomatic antiplatelet drug users, status of gastric atrophy should also be considered against severe gastroduodenal mucosal injury.

Fatal adverse drug reactions of anticancer drugs detected by all-case post-marketing surveillance in Japan.

All-case post-marketing surveillance of newly approved anticancer drugs is usually conducted on all patients in Japan. The present study investigates whether all-case post-marketing surveillance identifies fatal adverse drug reactions undetected before market entry. We examined fatal adverse drug reactions identified via all-case post-marketing surveillance by reviewing the disclosed post-marketing surveillance results, and determined the time points in which the fatal adverse drug reactions were initially reported by reviewing drug labels. We additionally scanned emergency alerts on the Japanese regulatory authority website to assess the relationship between all-case post-marketing surveillance and regulatory action. Twenty-five all-case post-marketing surveillances were performed between January 1999 and December 2009. Eight all-case post-marketing surveillances with final results included information on all fatal cases. Of these, the median number of patients was 1287 (range: 106-4998), the median number of fatal adverse drug reactions was 14.5 (range: 4-23). Of the 111 fatal adverse drug reactions detected in the eight post-marketing surveillances, only 28 (25.0%) and 22 (19.6%) were described on the initial global and the initial Japanese drug label, respectively, and 58 (52.3%) fatal adverse drug reactions were first described in the all-case post-marketing surveillance reports. Despite this, the regulatory authority issued only four warning letters, and two of these were prompted by case reports from the all-case post-marketing surveillance. All-case post-marketing surveillance of newly approved anticancer drugs in Japan was useful for the rigorous compilation of non-specific adverse drug reactions, but it rarely detected clinically significant fatal adverse drug reactions.

Phylodynamic analysis reveals CRF01_AE dissemination between Japan and neighboring Asian countries and the role of intravenous drug use in transmission.

BackgroundOne major circulating HIV-1 subtype in Southeast Asian countries is CRF01_AE, but little is known about its epidemiology in Japan. We conducted a molecular phylodynamic study of patients newly diagnosed with CRF01_AE from 2003 to 2010.MethodsPlasma samples from patients registered in Japanese Drug Resistance HIV-1 Surveillance Network were analyzed for protease-reverse transcriptase sequences; all sequences undergo subtyping and phylogenetic analysis using distance-matrix-based, maximum likelihood and Bayesian coalescent Markov Chain Monte Carlo (MCMC) phylogenetic inferences. Transmission clusters were identified using interior branch test and depth-first searches for sub-tree partitions. Times of most recent common ancestor (tMRCAs) of significant clusters were estimated using Bayesian MCMC analysis.ResultsAmong 3618 patient registered in our network, 243 were infected with CRF01_AE. The majority of individuals with CRF01_AE were Japanese, predominantly male, and reported heterosexual contact as their risk factor. We found 5 large clusters with ≥5 members and 25 small clusters consisting of pairs of individuals with highly related CRF01_AE strains. The earliest cluster showed a tMRCA of 1996, and consisted of individuals with their known risk as heterosexual contacts. The other four large clusters showed later tMRCAs between 2000 and 2002 with members including intravenous drug users (IVDU) and non-Japanese, but not men who have sex with men (MSM). In contrast, small clusters included a high frequency of individuals reporting MSM risk factors. Phylogenetic analysis also showed that some individuals infected with HIV strains spread in East and South-eastern Asian countries.ConclusionsIntroduction of CRF01_AE viruses into Japan is estimated to have occurred in the 1990s. CFR01_AE spread via heterosexual behavior, then among persons connected with non-Japanese, IVDU, and MSM. Phylogenetic analysis demonstrated that some viral variants are largely restricted to Japan, while others have a broad geographic distribution.

FRI0320 Pregnancy Outcomes in Rheumatoid Arthritis Patients Treated with Tocilizumab

BackgroundBiological agents (“biologics”), such as anti-tumor necrosis factor (TNF) agents and interleukin-6 (IL-6) inhibitors, have been widely used in recent years for the treatment of rheumatoid arthritis (RA) to achieve...

Effects of Japanese herbal crude drug, combined extract of Sasa albo-marginata leaves, Japanese red pine leaves and ginseng roots on gene expression in hypercholesterolemic rat liver

Effects of Japanese herbal crude drug, combined extract of Sasa albo-marginata leaves, Japanese red pine leaves and ginseng roots on gene expression in hypercholesterolemic rat liver

Comparison of global versus Asian clinical trial strategies supportive of registration of drugs in Japan

The number of worldwide and Asian multiregional clinical trials (MRCTs) submitted for Japanese New Drug Applications increased markedly between 2009 and 2013, with an increasing number performed for simultaneously submission in the USA, EU, and Japan. Asian studies accounted for 32% of MRCTs (14/44 studies) and had comparatively small sample sizes (<500 subjects). Moreover, the number of Japanese subjects in Asian studies was 2.1- to 13.4-fold larger than the sample size estimated using the method described in Japanese MRCT guidelines, whereas the ratio for worldwide studies was 0.05- to 4.9-fold. Before the introduction of this guidelines, bridging or domestic clinical development strategies were used as the regional development strategy in accordance with ICH E5 guidelines. The results presented herein suggest that Asian studies were conducted when the drug had already been approved in the US/EU, when phase 3 clinical trials were not be planned in the USA/EU, when there was insufficient knowledge of ethnic differences in drug efficacy and safety, or when Caucasian data could not be extrapolated to the Japanese population. New strategies with Asian studies including the Japanese population could be conducted instead of Japanese domestic development strategy.

Pharmaceutical company perspectives on current safety risk communications in Japan

In 1987, a group infection of hepatitis in patients receiving a contaminated fibrinogen product was first reported to the Japanese regulatory agency. Eventually, this serious drug incident involved more than 10,000 cases of infection. In response, the Government of Japan established a responding inspection committee in 2008 to make recommendations for the restructuring of drug regulatory administration. The final report was issued in 2010. One agenda item of this restructuring was the improvement of drug-related safety risk communications. Our research group on drug safety risk communications, which is funded by the Government of Japan, surveyed pharmaceutical companies regarding their perspective on current risk communications. The survey was conducted using an anonymous questionnaire developed for this study which included the three operational domains of targets, contents, and measures of drug risk communication. Fifty-two of the 74 member companies of the Post-marketing Surveillance Subcommittee of the Japan Pharmaceutical Manufacturer’s Association participated, and this response rate of more than 70% was considered sufficient to ensure the external validity of the survey results. Results showed that the most highly prioritized aspect of risk messaging was the strength of evidence, and that outcome evaluation of risk communication gained recognition. Further, while physicians and pharmacists were the most prioritized communication targets, pharmacovigilance departments devoted the most resources to regulators, at more than 30%. The Internet was recognized as a useful public source of risk information, whereas Drug Guides for Patients delivered on the web were considered under-recognized. Further discussion of these results with the aim of enhancing the restructuring of the Japanese drug regulatory administration system are warranted.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-3-51) contains supplementary material, which is available to authorized users.

PMDA update: the current situation and future directions

The Pharmaceuticals and Medical Devices Agency (PMDA) is a Japanese drug regulatory agency, sharing responsibilities with the Ministry of Health, Labour and Welfare. Its mission is to protect the public health by assuring safety, efficacy and quality of pharmaceuticals and medical devices. This paper introduces PMDA's current situation (until spring 2012) including its organisational structure, status of product review and safety measures, regulatory science, and international activities.

Prevalence of New Designer Drugs and Their Legal Status in Japan

In recent years, many analogs of narcotics have been widely distributed as easily available psychotropic substances and have become a serious problem in Japan. To counter the spread of these non-controlled substances, the Pharmaceutical Affairs Law in Japan was amended in 2006 to establish a new category; Designated Substances in order to more strictly control these substances. In April 2007, 31 compounds and 1 plant were first controlled as Designated Substances. Before 2007, the major compounds distributed in the Japanese illegal drug market were tryptamines, phenethylamines and piperazines. Alkyl nitrites, such as isobutyl nitrite and isopentyl nitrite, were also widely distributed. After they were listed as Narcotics or Designated Substances in 2007, these compounds, especially the tryptamines, quickly disappeared from the market. In their place, cathinone derivatives have been widely distributed, as well as different phenethylamines and piperazines. Additionally, in recent years, new herbal products containing synthetic cannabinoids have appeared globally. As at July 2012, 78 substances (including 1 plant; Salvia divinorum) were listed in the category of Designated Substances. They were 13 tryptamines, 17 phenethylamines, 11 cathinones, 4 piperazines, 23 synthetic cannabinoids, 6 alkyl nitrites, 3 other compounds and 1 plant. In this review, we show our survey of the spread of new designer drugs in Japan, focusing especially on synthetic cannabinoids and cathinone derivatives. Also, the prevalence and legal status of these substances in other countries will be presented.

&lt;b&gt;日本の医薬品添付文書における使用上の注意（臨床検査結果に及ぼす影響，過量投与，臨床成績，その他の注意）の記載内容に関する研究&lt;/b&gt;

&lt;b&gt;日本の医薬品添付文書における使用上の注意（臨床検査結果に及ぼす影響，過量投与，臨床成績，その他の注意）の記載内容に関する研究&lt;/b&gt;

クリアランス理論に基づいた医薬品情報の評価と提供に関する研究

Renal dysfunction and drug-drug interactions (DDIs) can affect the clearance of various drugs from the body; however, these effects are difficult to sufficiently evaluate in clinical studies. This article outlines our recent approaches to improve the method of evaluating and providing the drug information on the effects of renal dysfunction and DDIs. These approaches aim to optimize the drug regimens of patients with renal dysfunction and to improve the management of DDIs. The renal excretion ratio (RR) is required to predict alterations in drug clearance in patients with renal dysfunction. However, the estimation of RR requires pharmacokinetic information that is not always provided in the Japanese drug package inserts or interview forms.A systematic approach to predict changes in drug clearance due to DDIs of the cytochrome p450 (CYP) is described. Uniquely, this method uses a small number of parameters, which are only obtained by in vivo DDI studies, i.e., the contribution ratio of CYPs to oral clearance of substrates (CR), the inhibition ratio of inhibitors (IR) or the increase in clearance by induction (IC). Changes in oral clearance for any combination of drugs can be predicted once these parameters have been calculated for each drug. These predictions were used to construct a pharmacokinetic interaction significance classification system (PISCS) to evaluate the clinical risk of DDIs in daily therapy.

Darbepoetin alfa for the treatment of anemia in children undergoing peritoneal dialysis: a multicenter prospective study in Japan

Darbepoetin alfa (DA) is an attractive alternative to recombinant human erythropoietin (rHuEPO) in managing renal anemia. Since DA has not been approved by the appropriate Japanese drug regulatory agencies for the indication of renal anemia in children in Japan, we have conducted a multicenter prospective study to determine the efficacy and safety of DA in Japanese children undergoing peritoneal dialysis (PD). Pediatric patients subcutaneously receiving rHuEPO were switched to DA treatment for a period of 28 weeks. The conversion to the initial dose of DA was calculated as 1 μg DA for 200 IU rHuEPO, and DA was administered intravenously once every 2 weeks. The target hemoglobin (Hb) concentration was defined as 11.0 to ≤13.0 g/dL. In some patients, the dose of DA was adjusted appropriately to achieve this target level, and/or the dosing frequency changed to once every 4 weeks. In the 25 patients switched from rHuEPO to DA the mean Hb concentration increased from 9.9 ± 1.0 to 11.1 ± 1.0 g/dL at 8 weeks following commencement of the DA treatment. The target Hb concentration was achieved in 88 % of these patients, and 60 % maintained this target value on completion of the study. The dosing frequency was extended to once every 4 weeks in 60 % of patients. Twenty-four adverse events were noted in 11 of 25 patients (44 %); however, there was no causality between DA and adverse events. The results of this study suggest that intravenous administration of DA once every 2 or 4 weeks is an effective and safe treatment for renal anemia in Japanese children undergoing PD.