Japanese Drug Research Articles

SY4-5 - Kaizen: An Approach for Improving the Environment for Early Drug and Device Development in Japan

ABSTRACT In Japan, the notorious drug lag, i.e. delay in the time required for the approval of drugs, for new drug applications and supplemental new drug application approvals has recently become a major social issue. One study reported that the delay between the approval of a new drug in the United States versus approval of the same drug in Japan was ∼2.5 years. Some of the many factors that are responsible for this Japanese drug lag are as follows: unrefined development of investigational compound in preclinical studies, delays in initiating drug development in terms of phase I registration trials, larger and dubious costs of registration trials, bureaucratic and time-consuming paper work, inadequate life science-related human resource employment and infrastructure, connection of basic medical research institution with medical institution, rigidity of regulatory agency stance for drug development, extended length of the regulatory review period in Japan, necessity of revising related acts, less grant support for investigator initiated early phase trials, public health insurance systems, and insufficient provision of information pertaining to phase I registration trials to general public. Currently, academia, industries, and regulatory agencies continue to implement measures for overcoming many of the existing barriers to becoming more competitive at the global level. The Ministry of Health, Labour and Welfare has selected two core centers (Kitazato university, Keio University) for global clinical studies and five core centers for the early development of pharmaceuticals and medical devices. For the centralization of early drug development resources, core centers need to ensure faster, smarter, and cheaper development measures; further translational research and collaboration between core centers and regulatory agencies are required in order to meet the needs of global industries, venture companies, and institutes.

Inclusion of Human Intravenous Study Data in New Drug Applications—Impact of the Japanese Guidance

Human pharmacokinetic study after intravenous (i.v.) administration is inevitable in calculating basic pharmacokinetic parameters such as bioavailability, clearance, and distribution volume. However, i.v. data are not always included in the dossier, although the regulatory guidance recommends the inclusion of i.v. studies for Japanese new drug applications. We investigated the adherence to this guidance on the inclusion of i.v. data along with various factors. Logistic regression analyses were carried out on 117 new oral drugs approved in Japan between 1999 and 2009. Inclusion of i.v. data conspicuously increased after the issuance of the guidance for self-originated drugs developed by Japanese firms [odds ratio (OR) = 30-41). Moreover, drugs exhibiting large interindividual variations in pharmacokinetics showed a positive association (OR = 4.1-8.2), whereas solubility did not show notable association (OR = 1.0) with inclusion of i.v. data. Inclusion of i.v. data was not associated with physicochemical feasibility, but the developer's willingness to comply with the guidance seems to be involved.

Network analysis of adverse drug interactions.

Harmful effects associated with use of drugs are caused as a result of their side effects and combined use of different drugs. These drug interactions result in increased or decreased drug effects, or produce other new unwanted effects and are serious problems for medical institutions and pharmaceutical companies. In this study, we created a drug-drug interaction network from drug package inserts and characterized drug interactions. The known information about the potential risk of drug interactions is described in drug package inserts. Japanese drug package inserts are stored in the JAPIC (Japan Pharmaceutical Information Center) database and GenomeNet provides the GenomeNet pharmaceutical products database, which integrate the JAPIC and KEGG databases. We extracted drug interaction data from GenomeNet, where interactions are classified according to risks, contraindications or cautions for coadministration, and some entries include information about enzymes metabolizing the drugs. We defined drug target and drug-metabolizing enzymes as interaction factors using information on them in KEGG DRUG, and classified drugs into pharmacological/chemical subgroups. In the resulting drug-drug interaction network, the drugs that are associated with the same interaction factors are closely interconnected. Mechanisms of these interactions were then identified by each interaction factor. To characterize other interactions without interaction factors, we used the ATC classification system and found an association between interaction mechanisms and pharmacological/chemical subgroups.

日本の薬価制度：イノベーションと保険償還の狭間で

日本の薬価制度：イノベーションと保険償還の狭間で

Approaches to Japanese Dose Evaluation in Global Drug Development: Factors That Generate Different Dosages Between Japan and the United States

Drug development in Japan is shifting from a bridging strategy to a global strategy, and the number of multiregional trials in which Japan is included is increasing every year. The Japanese drug regulatory authority requires that data be collected in Japanese populations, and therefore dose-response studies of various drugs are frequently conducted in Japan. However, the current standard for adequate dose-finding processes may sometimes hinder the timely participation of Japan in these multiregional trials. We studied the development approaches and review patterns of 99 new molecular entities (NMEs) approved in 2003-2008 and have identified some common factors that result in differences in approved dosages in Japan as compared with other countries, such as dose-response study design, pharmacokinetics, and the timing of development. The findings of our research will serve as an initial information base on which to build an efficient global drug development strategy in Japan.

Delays in psychiatric drug development in Japan

The lag in the approval and development of psychiatric drugs between Japan and other countries has been a major issue both for patients with psychiatric diseases and for psychiatrists. The objective of this study was to analyse factors contributing to delays in launching new psychiatric drugs in Japan. We analysed data from Japan, the USA, and the UK for the approval of 23 standard psychiatric drugs and examined potential factors that might have contributed the delay of their launch. Of the 23 standard psychiatric drugs, all of which were approved in the USA and the UK, only 13 were introduced in Japan between September 2000 and July 2011. None of their development strategies adopted the ICH E5 guideline on simultaneous development of drugs on a global scale. Twelve of the 13 drugs (not including atomoxetine) were approved in Japan after their approval in the USA and the UK. The median review time (from approval application to approval) of these 13 drugs in Japan was 23 months, which was considerably longer than those of the US Food and Drug Administration and European Medicines Agency (10·0 and 13·5 months, respectively). The 10-13-month difference in review time cannot explain the overall 87- and 51-month delay in Japan after approval in the USA or UK. There remains a large gap between Japan and Western countries, such as the USA and the UK, with regard to access to standard psychiatric drugs, despite several important reforms in the Japanese drug approval system.

The Japanese drug master file

Pharmaceutical market in Japan is the largest in Asia by value. ICH comprises three developed regions namely USA, Europe, and Japan. Though majority of regulations are harmonized, Japan’s regulations are yet less explored compared to USA and Europe perhaps due to language barriers. Sharing of vital technological information to the drug product manufacturer remains a cause of concern to the manufacturers of ingredients and packaging components. Master files are voluntary vehicles for conveying product and manufacturing information from suppliers and contractors directly to regulators to support new drug and biologic product review, and may have open and closed sections. The latter contains confidential information for regulator’s reference. Japan has master file systems that accommodate a broader range of drug and components like packaging materials. Japan added a master file system similar to the US model by updating its regulatory process under the 2005 Pharmaceutical Affairs Law. The accreditation of manufacturing facility is one of the very unique features of master file system as unlike US and Europe, for Japan facility approval process starts well before the submission of the actual drug master file. The stability requirements involve more sample analysis compared to the other international regulatory compliance requirements. Point has to be noted that data equivalent to module 2 of common technical document and application form are required to be translated in Japanese language. However, the quality section (module 3) can be submitted in English language. Understanding of master file system is important for companies entering into the Japanese market. The master file system of Japan is discussed in this article.

A second-tier performance: reflections on Japan's pharmaceutical industry, 1945–2005

While Japan has led the world in certain high-technology industries, such as automobiles and electronics, it has remained a minor player in the global pharmaceutical industry. Japan's leading pharmaceutical firms invest less in R&D and record lower sales than leading global firms. Japan remains a net importer of pharmaceuticals and few Japanese drugs are found outside the country. The global pharmaceutical industry is led by firms from the United States, the United Kingdom and Switzerland, rather than those from Japan. This article explains why the pharmaceutical industry has remained largely in the second tier of Japan's dual economy. For the purposes of this paper, the dual economy refers to the pronounced divide observed between the globally competitive and non-competitive sectors of the Japanese economy. Japan's pharmaceutical industry long subsidised other sectors, including those in the competitive tier, by providing medicines at low prices for a universal health care system. This played a critical role in shaping the industry's domestic orientation. While no single reason explains why pharmaceuticals did not become one of Japan's first tier industries, the major reasons lay in the smaller size of Japanese firms, the lack of R&D incentives, and the government's protectionist policies.

Impact of “Guidance for Industry: Clinical Pharmacokinetic Studies of Pharmaceuticals” on New Drug Approvals of Central Nervous System Drugs in Japan

Human pharmacokinetic study after intravenous (i.v.) administration is inevitable in calculating basic pharmacokinetic parameters such as bioavailability, clearance, and distribution volume. However, i.v. data are not always included in the dossier, although the regulatory guidance recommends the inclusion of i.v. studies for Japanese new drug applications. We investigated the adherence to this guidance on the inclusion of i.v. data along with various factors. Logistic regression analyses were carried out on 117 new oral drugs approved in Japan between 1999 and 2009. Inclusion of i.v. data conspicuously increased after the issuance of the guidance for self-originated drugs developed by Japanese firms [odds ratio (OR) = 30–41). Moreover, drugs exhibiting large interindividual variations in pharmacokinetics showed a positive association (OR = 4.1–8.2), whereas solubility did not show notable association (OR = 1.0) with inclusion of i.v. data. Inclusion of i.v. data was not associated with physicochemical feasibility, but the developer's willingness to comply with the guidance seems to be involved.

Delays in Neurological Drug Development in Japan

The lag in the approval and development of neurological drugs between Japan and other countries has been a major issue for patients with neurological diseases. The objective of this study was to analyze the factors contributing to the delay in the launching of neurological drugs in Japan. We analyzed data from Japan and the US for the approval of 36 standard neurological drugs and examined the potential factors that may cause the delay of their launch. Of the 36 standard neurological drugs, all of which were approved in the US, only 21 were introduced in Japan from June 1999 to April 2010, whereas the other 15, whose indications were Alzheimer disease, epilepsy, migraine, multiple sclerosis, and Parkinson disease, remained unapproved. The US led Japan in the number of introductions (20 versus 1), with introductions in Japan occurring at a median of 87 months after introductions in the US. Japan's review time of new drug applications (23 months) could not explain this lag. In 15 of the 21 approved drugs, the application data package included overseas data. The mean review time of these 15 drugs was significantly shorter than that of the other 6 drugs without overseas data. The maximum daily doses of 7 of the drugs were higher in the US than in Japan. These results show that there is still a large gap between Japan and the US with regard to access to standard neurological drugs, despite several important reforms in the Japanese drug approval system.

The generic drug market in Japan: will it finally take off?

Historically, brand-name pharmaceuticals have enjoyed long periods of market exclusivity in Japan, given the limited use of generics after patent expiration. To improve the efficiency of the health-care system, however, the government has recently implemented various policies aimed at increasing generic substitution. Although this has created expectations that the Japanese generic drug market may finally take off, to date, generic usage has increased only modestly. After reviewing the incentives of key market participants to choose generics, we argue that previous government policies did not provide proper incentives for pharmacies to boost generic substitution. We offer some recommendations that may help to increase generic usage.

Fixed drug eruption caused by the Japanese herbal drug kakkonto

Herbal drugs are now widely used throughout the world. The general public tends to believe these agents to be safe because of their natural origin; thus, they are used frequently. However, the side effects of many of these potent chemicals may be significant. Several cases of fixed drug eruption (FDE) caused by herbal drugs have been reported. We herein report a case of FDE caused by kakkonto.

Report of the Inquiry into Natural Resources of Chinese and Japanese Crude Drugs (II)

Report of the Inquiry into Natural Resources of Chinese and Japanese Crude Drugs (II)

Study on a traditional Japanese drug Swertiae herba

Study on a traditional Japanese drug Swertiae herba

Chemical constituents and DNA sequence analysis of a psychotropic herbal product

In recent years, the distribution of a variety of psychotropic products, especially “spice” and “herbal blends,” which are advertised to have narcotic-like effects, has become more widespread in the Japanese illegal drug market. We recently found two synthetic annabinoids, cannabicyclohexanol and JWH-018, that serve as adulterants in herbal products purchased via the Internet. In this study, we focused on a herbal product being sold as incense, which showed unknown components by liquid chromatography-mass spectrometry (LC-MS). The product did not show any peak corresponding to the above synthetic cannabinoids, but seven other peaks were identified by high-performance liquid chromatography and LC-MS. We identified them as N-methyltyramine (1), (R)-normacromerine (2), (R)-macromerine (3), (S)-vasicine (4), mescaline (5), harmaline (6), and harmine (7) by polarimetry, LC-MS, gas chromatography-mass spectrometry, high-resolution mass spectrometry, and nuclear magnetic resonance spectroscopy. We also used DNA sequence analyses to identify the plant species of the product. As a result of the sequencing of trnL-F, internal transcribed spacer (ITS), and rpl16 intron regions, three sequences derived from Coryphantha macromeris (Cactaceae), Peganum harmala (Zygophyllaceae), and Turnera diffusa (Turneraceae) were observed. Compounds 2 and 3, both phenethylamines, were reported to cause hallucinogenic effects and are frequently found in Coryphantha genus (Cactaceae). Therefore, the plant source of these compounds was considered to be C. macromeris. Compound 5 is known to be a psychoactive phenethylamine found in peyote (Lophophora williamsii) and San Pedro cactus (Trichocereus pachanoi). The β-carboline alkaloids 6 and 7 are known to be found in the seeds of P. harmala. Therefore, there seems to be no contradiction between the chemical constituents and the plant species estimated by DNA analyses, except for compound 5. This is the first report dealing with identification of the psychoactive cactus C. macromeris and its constituent compounds in a herbal product distributed in the illegal drug market.

Chemical analysis of synthetic cannabinoids as designer drugs in herbal products

Several synthetic cannabinoids were found in 44 of 46 different kinds of herbal products that are currently distributed on the illegal drug market in Japan due to their expected narcotic effects. Gas chromatography–mass spectrometry (GC-MS) and liquid chromatography–mass spectrometry (LC-MS) analyses indicated that most of the products contained two major synthetic cannabinoids: (1 RS,3 SR)-3-[2-hydroxy-4-(2-methylnonan-2-yl)phenyl]cyclohexan-1-ol, renamed cannabicyclohexanol with the agreement of Pfizer Inc., and/or 1-naphthalenyl(1-pentyl-1 H-indol-3-yl)methanone, named JWH-018. Oleamide ( cis-9,10-octadecenoamide), which is an endogenous cannabinoid, was also detected in 7 products. Additionally, two synthetic cannabinoids were identified as minor components in some products. One was (1 RS,3 SR)-3-[2-hydroxy-4-(2-methyloctan-2-yl)phenyl]cyclohexan-1-ol, which is named CP-47,497 and is a homolog of cannabicyclohexanol. The other was 1-naphthalenyl(1-butyl-1 H-indol-3-yl)methanone, which is named JWH-073 and is a homolog of JWH-018. These compounds were reported as synthetic cannabinoids possessing pharmacological cannabimimetic activity. The concentrations of cannabicyclohexanol, JWH-018 and oleamide in the products ranged from 1.1 to 16.9 mg/g, 2.0 to 35.9 mg/g and 7.6 to 210.9 mg/g, respectively, and showed considerable variation. In this study, details of the analysis and identification of these synthetic cannabinoids in herbal products being sold on the Japanese drug market are described.

Biopharmaceutical entrepreneurship in two Japanese and French bioclusters: Differences in founder profiles and experience

Favoured by genetic engineering breakthroughs, a new type of firm has emerged in the pharmaceutical industry. New Biotechnology Firms (NBFs) are ‘bridging institutions', accelerating the commercialisation of science from academia to the pharmaceutical market and facilitating technological incursions into drug development or therapeutic paths yet unexplored. As such, they have raised industrial and political interest around the world. Successes can be outstanding and some countries seem to offer much more favourable environments than others. Countries' performances are usually benchmarked against their provision of favourable resources and institutions, but this article takes an alternative route by considering the entrepreneurial side of NBF as a major factor in their emergence. ‘Entrepreneur biographies' and firm creation experience were collected in two comparable bioclusters in France (Evry) and Japan (Kobe), on 11 Japanese and French drug development NBFs. The result shows an interesting variation in backgrounds and motivations, in that almost all our French entrepreneurs came from public research institutes, whereas a large share of the Japanese entrepreneurs came from large pharmaceutical companies. This finding questions the universal nature of entrepreneurship in biopharmaceutical firms and invites consideration for a model of entrepreneurship that is socially embedded in a country's specific institutional and historical factors.

Degradation of N-hydroxy-3,4-methylenedioxymethamphetamine in aqueous solution and its prevention

N-Hydroxy-3,4-methylenedioxymethamphetamine ( N-OH-MDMA) is a lesser known psychedelic drug that has recently circulated in the Japanese illicit drug market. From the instability of the similarly structured N-hydroxy-3,4-methylenedioxyamphetamine ( N-OH-MDA) in neutral-to-basic aqueous solution, it was presumed that N-OH-MDMA would also degrade in aqueous solution. The aims of this study were: (i) investigation of the degradation of N-OH-MDMA in aqueous solution and its prevention, (ii) identification of the degradation products, (iii) determination of the p Ka for the conjugate acid of N-OH-MDMA, and (iv) evaluation of liquid–liquid extraction recovery. N-OH-MDA was also included in some of these studies. N-OH-MDMA degraded to 14.9% of initial concentration after 2 h storage in pH 10 buffer solution at 22 °C. This degradation was completely inhibited at least for 2 h by addition of l-ascorbic acid, a strong reactive oxygen scavenger. These findings indicate that reactive oxygen species in alkaline solution were involved in N-OH-MDMA degradation. N-OH-MDA, α-methyl-( N-methylene)-3′,4′-methylenedioxybenzeneethanamine and 3′,4′-methylenedioxyphenyl-2-propanone oxime were found as degradation products of N-OH-MDMA in alkaline solution. The p Ka for the conjugate acid of N-OH-MDMA was determined by titration to be 5.52, which was much lower than that reported for 3,4-methylenedioxymethamphetamine (p Ka = 10.38). Excellent recoveries for N-OH-MDMA and N-OH-MDA (>98%) were achieved by extraction with ethyl acetate or chloroform from a basic buffer (pH 10) solution containing 0.1% l-ascorbic acid.

GC/MS analysis of an herbal dietary supplement containing ephedrine

An unconscious 20-year-old female was admitted to hospital with a heart rate of 164, a blood pressure of 132/90 mmHg, and hypokalemia. “Triage” urine screening tests were negative on arrival and 12 h later. The next day, her SGOT and SGPT levels rose remarkably; however, on the third day, the patient regained consciousness. Two Japanese OTC drugs and an American herbal dietary supplement (“7th heaven”) were found in her room. The supplement and the patient’s samples were analyzed using GC/MS. Ephedrine (2.32 mg/g) and caffeine (17.96 mg/g) were detected in the supplement and in the patient’s serum (0.627 mg/L, 383 mg/L, respectively), as well as acetaminophen, bromvalerylurea, and etenzamide, which are constituents of the OTC drugs. The serum ephedrine concentration was above the therapeutic level but did not reach the fatal level. The acetaminophen concentration was sufficient to cause liver damage. Although a prescription is necessary to obtain products containing ephedrine in Japan, this patient had no prescription. Thus, how the patient obtained the drug and the amount ingested were unclear. Information about acquisition of drugs via the Internet or magazine advertisements is constantly changing and unreliable. Thus, it is indispensable to analyze unfamiliar supplements found with patients.

Crystal clear: a landmark pharma patent victory in Japan

In a landmark decision, the Intellectual Property High Court of Japan enforced a Japanese pharmaceutical patentee's crystal form patent to stop a Japanese generic drug maker, even though the basic substance patent on its blockbuster antibiotic compound had expired some 5 years earlier. Pharmaceutical companies are extremely dependent on rigorous patent protection against relentless generic competition resulting from recently increasing patent expirations. The article provides a snapshot of similar crystal form patent litigation developments in the commercially important pharmaceutical patent jurisdictions such as Japan, the USA, and Europe. Pharmaceutical patentees can now utilize crystal form or second generation patents as part of their Japanese patent strategy to enlarge the scope or length of patent protection over the product.