Historical sketch of modern pharmaceutical science and technology (Part 3). From the second half of the 19th century to World War II

The history of modern pharmaceutical science and technology, from the second half of the 19th century to the end of World War II, is divided into nine sections for the purpose of discussion. 1. The European medical and pharmaceutical science and technology at the end of the 19th century is reviewed. Pharmacology, bacteriology and biochemistry were built in this period. 2. The Meiji Government accepted Western medicine and medical law and regulations in 1883. Consequently, the Japanese physician changed from Eastern (Kanpooi) to Western (Seiyooi). 3. Modern scientific and engineering education had been accepted in America, England, Germany, and France etc. Foreign scientists and engineers (Oyatoi-gai-kokujin) were educated by practice and theory. The Faculty of Engineering was established in the universities in Japan. This fact is one of the differences in the history of universities in Europe and America. 4. Pharmaceutical education in the Meiji period (1873-1911). Twenty-nine schools of pharmacy were built in this period. However, 20 schools of pharmacy had been closed. Pharmacy and pharmaceutical industry was not established in the Meiji era. 5. The profession of pharmacist in 1873-1944. The policy of medicine was changed by the Meiji Government in 1889, when Western physicians were allowed to prepare medicines for patients, and this practice continues today. Political and technological power of Japanese pharmacists was weak, so their role was not estimated. 6. Consequences of world War I, and the establishment of the pharmaceutical industry. The Sino-Japanese War (1894-95) and Russo-Japanese War (1904-05) were won fortunately. The first pharmaceutical company was established in 1885. At this times, many pharmaceutical manufacturing companies, which were converted from whole sale merchants, were built. Then started the manufacturing of commercial drugs. 7. Hygienic chemistry and some problems of public hygiene. The causes of diseses unique to Japan, such as beriberi (Katuke), were searched for in medical and agricultural laboratories. Dr. Suzuki discovered olizanine from rice bran, which was effective for deficiency of vitamin B1 disease. However, pharmaceutical scientists did not participate in this research. Hygienic and forensic chemistry were included in pharmaceutical departments. 8. Pharmaceutical scientific studies in Europe and Japan in the first half of the 20th century. The discovery of a drug for the treatment of syphilis by Ehrlich-Hata (1889), then chemotherapeutics were started. Adrenalin, the first isolated hormone, by Takamine (1900), after this time many hormones were discovered. The first Japanese pharmacists who studied abroad studied in Germany and came back to Japan. Then, they built the pharmaceutical sciences. Studies on natural products by chemistry and organic chemistry were started. 9. Pharmaceutical scientific and technology during 15 Years of War (1931-45). Since 1930, theoretical organic chemistry was developed in England and America. The discovery of chemotherapeutics and antibiotics (sulfonamides and penicillin) and studies on some vitamins and hormones proceeded during the 15 years of war (1931-45) at Tokyo and Kyoto Universities, and some institutes in China and Manchuria. Studies on anti-maralia, sulfonamides and penicillins were carried out.     

Japan-Specific Key Regulatory Aspects for Development of New Biopharmaceutical Drug Products

Japan represents the third largest pharmaceutical market in the world. Developing a new biopharmaceutical drug product for the Japanese market is a top business priority for global pharmaceutical companies while aligning with ethical drivers to treat more patients in need. Understanding Japan-specific key regulatory requirements is essential to achieve successful approvals. Understanding the full context of Japan-specific regulatory requirements/expectations is challenging to global pharmaceutical companies due to differences in language and culture. This article summarizes key Japan-specific regulatory aspects/requirements/expectations applicable to new drug development, approval, and postapproval phases. Formulation excipients should meet Japan compendial requirements with respect to the type of excipient, excipient grade, and excipient concentration. Preclinical safety assessments needed to support clinical phases I, II, and III development are summarized. Japanese regulatory authorities have taken appropriate steps to consider foreign clinical data, thereby enabling accelerated drug development and approval in Japan. Other important topics summarized in this article include: Japan new drug application-specific bracketing strategies for critical and noncritical aspects of the manufacturing process, regulatory requirements related to stability studies, release specifications and testing methods, standard processes involved in pre and postapproval inspections, management of postapproval changes, and Japan regulatory authority's consultation services available to global pharmaceutical companies.     

Drug policy in China. Transformations, current status and future prospects

The pharmaceutical sector in China developed rapidly with the implementation of the market-oriented economic reforms, which began at the end of the 1970s. From 1980 to 1988 the production of drugs quadrupled, subsequently increasing at an annual rate of 20%, and consumption of drugs correspondingly increased. The increase in drug production was largely a result of the increase in the number of pharmaceutical companies, particularly the number of private joint ventures, of which there were none in 1980 and 1900 in 1994, accounting for 37% of the total number of pharmaceutical companies. With the transformation of the Chinese pharmaceutical market, some new problems have appeared. The low efficiency of pharmaceutical companies, poor-quality drugs, unfair competition and misuse of drugs have been of great concern to the Chinese government. Some countermeasures have been taken, but the problems remain. Increases in the age of the Chinese population, increases in income and changes in disease patterns, together with membership of the World Trade Organization will promote the development of the pharmaceutical market. However, health-insurance reform, an essential drug list, the separation of drugs from services, and controls on the increases in hospital revenue will reduce the demand for drugs. Pharmaceutical companies in China face both opportunities and challenges. The trend in development of the pharmaceutical market depends on the outcome of the interaction between the factors that increase, and those that decrease, the demand for drugs. While the general trend is towards an increase in the demand for drugs and the expansion of the pharmaceutical market, downward fluctuation is inevitable if effective health reforms of cost control are introduced nationwide.     

Social change and Pharmaceutical Affairs Law (PAL)

Former Japanese pharmaceutical laws, originally based on the Pharmaceutical Marketing and Handling Regulations enacted in 1874 were in operation for many years before World War II. However, in order to address several drug issues, such as poor drug quality and insufficiences regarding the role of pharmacists during the War, the laws needed to be unified and revised. In this paper, we analyzed the record of discussions held by the Imperial Diet on the bill for the Pharmaceutical Affairs Law (PAL) in 1943. This is also regarded as the origin of the current PAL (LawNo.145 in 1960). Through this analysis, we tried to clarify the relationship between the social change and the role of PAL in society. During the War, the bill was discussed, aiming at the improvement of both human resources who treated drugs, and the quality of drug materials. Diet members discussed three main points, namely, "the duty of pharmacists", "the mission of the Japan Pharmaceutical Association" and "the quality control of pharmaceutical products". Notably, the bill pharmacists are required not only to dispense drugs, a role they had previously, but also to manage drug and food hygiene through the quality control of pharmaceutical products and the inspection of food and drink, in order to improve the public health in Japan. Originally, the law was passed to deal with the extraordinary circumstances during the War, but through our analysis, we found that they proactively improved the role of the law to comply with various drug issues raised during the War, the rapid change of the pharmaceutical hygiene concept and the social transformation.     

A history of a hundred years of pharmaceutical education in Japan

The history of a hundred years of pharmaceutical education in Japan is divided into six periods for the purposes of discussion. 1. Founding period of the pharmaceutical education in the Meiji era (1873-1879) The Department of Manufacturing Pharmacy, Faculty of Medicine, University of Tokyo was established in 1873 (now, Faculty of Pharmaceutical Sciences, the University of Tokyo). The purpose of this school was for professional training to accommodate growing imported Western drugs. 2. Building period of the pharmaceutical education in the Meiji era. (1880-1911) The Pharmaceutical society of Japan (academic) was established in 1880, and then 13 years later (1893) the Japan Pharmaceutical Association (professional) was established. The order of establishments, first academic and then professional, was opposite of the history in European countries. Twenty-nine schools of pharmacy were built in the Meiji era, however 20 schools of pharmacy have been closed. 3. Developing period the pharmaceutical education in the Taisho era and half of the Showa era (1912-1944) Seventeen pharmaceutical colleges were built in these periods. Pharmaceutical chemistry, pharmacognosy, hygenic chemistry, and manufacturing chemistry were mainly taught in these schools of pharmacy, however pharmacology, bacteriology, and biochemistry were not taught in these schools. 4. Reform of pharmaceutical education system after the World War II (1945-1960) In 1949, the Japanese education system was reformed, and then 46 colleges and universities of pharmacy were built. Then, the number of students doubled to 8,000. Graduates from pharmaceutical colleges and universities, pharmaceutical departments were eligible to take the national pharmacists licence examination which was conducted by the Ministry of Health and Welfare. The standard of the pharmaceutical education system was revised in 1656, recommending that the single pharmaceutical departments at the colleges of pharmacy by replaced by three departments, pharmacy, manufacturing pharmacy and biological pharmacy. 5. Improvement and developement of pharmaceutical education (1961-1985) Many universities and colleges were founded, and there are currently 46 universities and colleges. Every year, some 8,000 people who study pharmacy at 14 national, 3 public and 29 private universities enter the profession on graduation. About 60 percent found jobs in the pharmaceutical industry, and the remainder work as pharmacists in hospitals and pharmacies. 6. Recent movements toward reform in pharmaceutical education (1986-present) Two amendments to the Medical Services Law in 1986 and 1992 have specified clearly the role to be played by pharmacists and pharmacies within their local medical service and has sharpened the distinction between medicine and pharmacy. Thus, in 1994, the period required for graduation is proposed by a committee of the Ministry of Health and Welfare, supplementing of the current 4-year undergraduate pharmacy course with a 2-year postgraduate master's degree course or a 6-year new pharmaceutical education system including practical training in a medical institution for a period of at least 6 months.     

Pharmacophore-based virtual screening: a review of recent applications

The global pharmaceutical industry is described as facing an ‘innovation crisis’ following the ‘go-go-pharma’ era; in other words, the problem is one of ‘more money and fewer products’. Nevertheless, patients worldwide are awaiting innovative drugs. Therefore, the pharmaceutical industry has a duty to discover and develop novel drugs and medical technologies. Through universal coverage and reform of the patent system, the Japanese pharmaceutical industry has expanded greatly in line with the Japanese economy. However, in terms of scale and R&D investment, the Japanese pharmaceutical firms have lagged behind the foreign multinationals, which have undergone successive mergers and acquisitions. Meanwhile, it is true that several Japanese firms are playing an active role in overseas markets with their own blockbusters. This paper analyses and gives an overview of new trends in Japan’s pharmaceutical industry within the global context.     

放射性核素示踪技术在化学创新药人体物质平衡中的应用

在化学创新药的研发过程中,低能量放射性核素（主要为14C）示踪技术可用于开展人体物质平衡研究,以明确用药后一定时间内药物及其代谢物的主要排泄途径（尿液还是粪便）及排泄回收率（需>90%）。该技术在创新药人体吸收、代谢及排泄研究中仍具有其他技术无法比拟的优势,在日本及欧美制药工业界已被广泛应用多年。本文简述放射性核素示踪的基本原理,回顾2018年以来在美国批准的新分子实体新药中应用该技术的情况,阐述放射性核素示踪技术在人体物质平衡研究中的应用及其在我国创新药研发中的前景。     

西安市中小型制药企业生产现状及发展方向的调查

目的 调查西安市中小型制药企业生产现状,为企业发展提供思路.方法 从2008年3月～2011年6月西安市中小型制药企业中随机抽取103家,采用自制问卷的形式对各家制药企业进行现场调查,问卷内容包括企业的基本情况构成、企业人员情况、质量管理及新药研发情况等,并对调查结果进行分析.结果 ①西安市中小型制药企业人员的组成方面,专科及以上学历占总人数＜1 0％的为39 (37.86％)家,10％～ 30％的为47 (45.63％)家;专业职称占总人数＜1 0％的为78 (75.73％)家;②对企业质量管理的追求方面,持续改进的为21 (20.39％)家,提升企业竞争能力的为23 (22.33％)家;③企业研发新产品新技术方面,有新技术需求的为81(7 8.64％)家,有自己研发机构的为9 0(87.38％)家,可以创新研发新药的为36(34.95％)家.结论 西安市中小型制药企业在人才结构上存在严重缺陷,企业的质量管理观念较差,企业研发新产品新技术明显不足.合理的人才梯队、具有自主知识产权的新药和严格的生产质量监控可以使中小型制药企业产品创新、技术创新、管理创新,走“专、精、特、新”的特色发展道路.     

A pilot study to build a database on seven anti-hypertensive drugs

PURPOSE: In Japan, all patients are able to see freely any clinics or hospitals. So clinical data of all patients have been stored at clinics, hospitals and medical institutes respectively. These patients' clinical course data stocks have not been combined with one another. There is no large-scale database, which has been available and has played its role in complementing spontaneous adverse drug reaction (ADR) reporting system. We tried to build an original database using anti-hypertensive drugs' data from Drug Use Investigation conducted for the Japanese Drug Re-examination application by every pharmaceutical manufacturer in conformity with Japanese Pharmaceutical Affairs Law and Related Regulation. METHODS: The 43 565 case data of seven anti-hypertensive drugs (one Ca-antagonist, one alpha-blocker, two beta-blockers, three ACE inhibitors) were kindly offered from seven manufacturers who were members of RAD-AR Council, Japan. After examining the data items and categories, they were standardized into common codes based on Japanese Drug Category Classification (JDCC), International Classification of Diseases 9 (ICD-9) and Japanese Adverse Drug Reaction Terminology (J-ART). As each manufacturer had a different coding method in accordance to manufacturer's own practice of data management, the original forms were divided into several datasets. The data processing and statistical analysis were conducted using Statistical Analysis System (SAS). RESULTS: (1) Technology and know-how to combine data coded by different methods were established for building a database that had never been tried in Japan. (2) The following are the by-products of the study: a) Onset of ADR concentrated in the early stage but onset of some disorders prevailed equally throughout the investigation period. b) Although the number of collected cases of anti-hypertensive drugs was 43 565, total number of administrated anti-hypertensive drugs reached to 70 714 because additional anti-hypertensive drugs were often used with subject drugs. CONCLUSION: There is no large-scale database of patients' clinical course in Japan. However, since the Japanese Drug Re-examination System started in 1979, almost eight million cases of Drug Use Investigation on about 700 drugs have been collected with enormous human power and huge expenditure for Japanese Drug Re-examination application by pharmaceutical manufacturers. New and more appropriate information will be detected by the database, built using Drug Use Investigation data that were collected only for the Japanese Drug Re-examination application.     

Transition of Japanese societies related to clinical chemistry in the mid-Showa period (1955-1980) (part 3) - related to the medical field

Remarkable progress in the Japanese clinical chemical field was observed in the mid-Showa period (1955-1980). Many biochemists, pharmacists, medical doctors, and medical technologists started their studies and reported their accomplishments in the clinical chemical societies during this period. I recently reported on the transition of pharmaceutical science societies in the clinical chemical field in JJHP, Vol. 35, No. 2, in 2000, and Vol. 36, No. 1, in 2001. In these reports, the transition of medical societies in the clinical chemical field and social insurance medical fee payments were discussed. The Japan Society of Clinical Pathology (JCCP) was started in 1951 and the Japanese Association of Medical Technologists (JAMT) in 1952. The former mainly consists of biochemists and medical doctors and the latter of medical technologists in Japanese hospitals. Because many clinical examinations in hospitals were undertaken with the support of instruments (for example, the Auto Analyzer AA-1), the Japan Society for Clinical Laboratory Automation (JSCLA) started in 1969. The Japan Committee for Clinical Laboratory Standards started in 1984. The Japan Medical Association helped to promote clinical chemical examinations in the medical field, especially since 1957, by increasing the social insurance medical fee payment.     

Perspectives on non-clinical safety evaluation of drug metabolites through the JSOT workshop

The prompt and appropriate safety assessment of drug metabolite(s) was mentioned in regulatory guidances such as an International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidance, entitled "Guidance on Non-clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals" (ICH M3(R2)) implemented in January 1 of 2011 in Japan, and has become a significant issue in the drug development. Upon release of ICH M3(R2) Step 4, a survey was conducted between March and April 2010 on the safety assessment of drug metabolites in 63 member companies of the Japan Pharmaceutical Manufacturers Association (JPMA). The Pharmacokinetics Team in the Non-Clinical Evaluation Expert Committee in JPMA conducted a questionnaire survey and compiled the results to comprehend how safety of drug metabolites are currently assessed at research-based pharmaceutical companies in Japan. The assessment of "Metabolites in Safety Testing" (MIST) can be divided into three stages based on the research purpose as follows: MIST 1 is a stage of estimating human drug metabolites and predicting their potential risks, MIST 2 is a stage of deciding the necessity for non-clinical safety studies, and MIST 3 is a stage of conducting non-clinical safety studies. In this paper, we propose typical approaches on safety assessment of metabolites that meet the purpose of each stage, considering the current level of scientific technology. Our proposals are based on the results from our survey and a symposium about the safety assessment of drug metabolites at the 37th annual meeting of the Japanese Society of Toxicology held in June 2010.     

A case for the adoption of pharmacoeconomic guidelines in Japan

In recent years, more and more Japanese pharmaceutical companies have been submitting pharmacoeconomic data to the government, following the official request that such data may help in setting pharmaceutical prices. The companies have cooperated because, by doing so, they could influence pricing decisions for new products. However, the quality of these data at present is considered to be poor and heavily biased. The introduction of pharmacoeconomic guidelines that outline a set of standardised factors to be included in evaluations are necessary, so that an appropriate comparison of the cost effectiveness of the many new drugs that are introduced into the Japanese market each year can be made. In addition to supporting the development of standardised guidelines, the Ministry of Health and Welfare should clarify how pharmacoeconomic data are to be used to aid policy decisions and also mandate the publication of pharmacoeconomic data.     

Molecular diagnostic patents January to September 1999: part 2 - infection targets

An analysis of molecular diagnostic patents published in the first nine months of 1999 shows that roughly two-thirds of documents from the top three companies (Innogenetics, Abbott Laboratories and Akzo Nobel) are focused on immunoassay technologies. However, this focus is shifting toward nucleic acid based approaches. Interestingly, companies with a strong emphasis on nucleic acid based approaches also own their own proprietary detection techniques, threatening Roche’s polymerase chain reaction (PCR) as the dominant technology. There is some evidence that the mainstream pharmaceutical companies are becoming active in nucleic acid-based technologies for infection targets, using these techniques to develop new drugs.     

Biotechnology and genetic engineering in the new drug development. Part I. DNA technology and recombinant proteins

Pharmaceutical biotechnology has a long tradition and is rooted in the last century, first exemplified by penicillin and streptomycin as low molecular weight biosynthetic compounds. Today, pharmaceutical biotechnology still has its fundamentals in fermentation and bioprocessing, but the paradigmatic change affected by biotechnology and pharmaceutical sciences has led to an updated definition. The biotechnology revolution redrew the research, development, production and even marketing processes of drugs. Powerful new instruments and biotechnology related scientific disciplines (genomics, proteomics) make it possible to examine and exploit the behavior of proteins and molecules.Recombinant DNA(rDNA) technologies (genetic, protein, and metabolic engineering) allow the production of a wide range of peptides, proteins, and biochemicals from naturally nonproducing cells. This technology, now approximately 25 years old, is becoming one of the most important technologies developed in the 20^th century.Pharmaceutical products and industrial enzymes were the first biotech products on the world market made by means of rDNA. Despite important advances regarding rDNA applications in mammalian cells, yeasts still represent attractive hosts for the production of heterologous proteins. In this review we describe these processes.     

Contribution of pharmacology for new drug application in Japan

The Organization for Pharmaceutical Safety and Research (OPSR), Pharmaceuticals and Medical Devices Evaluation Center (PMDEC), National Institute of Health Sciences and Ministry of Health, Labour, and Welfare (MHLW) are working together on the new pharmaceutical approval process in Japan for appropriate scientific approaches. The Consultation Division of OPSR helps the pharmaceutical companies to answer find solutions to their concerns about non-clinical and clinical trials in the new pharmaceutical development process. After a new pharmaceutical application, PMDEC evaluates the quality, efficacy, and safety of each pharmaceutical compound in the review process. Final judgment for approval is made by MHLW. Pharmacological mechanisms examined in non-clinical trials would be useful for selection of the appropriate end-point in the clinical trials. For safety assessment, International Conference of Harmonization (ICH) Guideline on Safety Pharmacology Studies was officially notified. According to pharmacological data on safety, clinical investigators can better design clinical trials to prevent patients from suffering serious adverse events. To development new epoch pharmaceuticals, continuous progress on pharmacological research will be indispensable. Further discussion among all interested parties such as pharmacological researchers, medical doctors, companies, and regulatory sites will be necessary and useful to develop more appropriate approaches in the pharmaceutical development process.     

Why has the use of health economic evaluation in Japan lagged behind that in other developed countries?

The aging population and the increasing availability of new medical technologies, particularly pharmaceuticals, have led to growing pressure on governments worldwide to contain healthcare costs. Increasingly, economic evaluation is used to aid decisions on the reimbursement and formulary access of drugs, and pharmaceutical companies are often required to demonstrate the cost effectiveness of their products. Canada and the UK are examples of countries that have successfully incorporated mandatory requirements for economic evaluations into the decision-making process in healthcare. Japan faces cost-containment issues for its health and welfare system similar to those seen elsewhere in the world. Despite this, economic assessments are not currently used in the allocation of drug budgets. Reasons why economic evaluations for healthcare have not yet been used routinely in Japan include governmental approaches to healthcare cost containment, the pricing of pharmaceuticals, the organisation of the healthcare system, attitudes of the medical profession, and limited knowledge and expertise. However, small but encouraging steps are now being taken towards the introduction of economic evaluations in Japanese medicine.     

The societal value of pharmaceuticals. Balancing industrial and healthcare policy

Pharmaceutical policy arises through an ongoing process of negotiation and interaction among the key players in the pharmaceutical market: consumers, industry, healthcare providers and government. There is constant discussion about the just distribution of reward between cost-containment goals and the goals of research and development in the pharmaceutical arena. All industrial countries are under pressure to control healthcare costs, but it is unclear how cost-containment policies will influence industrial policies for pharmaceuticals. The pharmaceutical industry is an easy target for governmental cost-containment policies. The industry is driven by 3 issues: access to consumers, access to new technology and new competitive realities. The launch of a new, innovative product that represents a significant therapeutic breakthrough is becoming increasingly difficult, and a major challenge for politicians and governments will be to balance the need for cost-effective use of drugs and the need to create a favourable climate for innovation. Previously, there was generally little competition between pharmaceutical companies, but those companies will now have to undergo fundamental and comprehensive changes. Particularly, it will be important to have extremely well developed and integrated management systems focusing on both consumers and costs.