Japanese Drug Research Articles

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.

Chemopreventative Effect of Hochu-ekki-to (TJ-41) on Chemically Induced Biliary Carcinogenesis in Hamsters

Bilioenterostomy is a common surgical technique that is widely used. Recently, clinical studies have revealed that biliary carcinomas can occur after bilioenterostomy. The present study was designed to evaluate whether hochu-ekki-to (TJ-41), a Japanese herbal drug, could prevent chemically induced biliary carcinomas in bilioenterostomized hamsters. Syrian golden hamsters were subjected to choledochojejunostomy and then received subcutaneous injections of N-nitrosobis(2-oxopropyl) amine every 2 weeks at a dose of 10 mg/kg. N-nitrosobis(2-oxopropyl) amine administration was started 4 weeks after surgery. The animals were simultaneously p.o. administered TJ-41 in water every day at a dose of 1000 mg/kg (TJ-41 group). The control hamsters were administered water alone. The hamsters were sacrificed 22 weeks after surgery, and the development of biliary carcinomas, the presence and degree of cholangitis, and the cell kinetic status of the biliary epithelium were evaluated histologically. Intrahepatic bile duct carcinomas developed in 15/17 (88%) hamsters in the control group and in only 8/17 (47%) hamsters in the TJ-41 group (P < 0.05). The degree of cholangitis was not different between the two groups. However, the proliferating cell nuclear antigen labeling index of the biliary epithelium in the TJ-41 group (6.46%) was significantly lower than the controls (9.67%) (P < 0.05). These findings indicated that TJ-41 reduced accelerated biliary epithelial cell kinetics after bilioenterostomy, resulting in the prevention of carcinogenesis. TJ-41 has a preventive effect on chemically induced carcinoma of the biliary tract after bilioenterostomy.

Problems in three Japanese drug users with Human Immunodeficiency Virus infection

Numbers of individuals infected with Human Immunodeficiency Virus (HIV) are increasing in Japan. The majority of them are Men who have sex with men and a part of them take drugs as 'Sex drug' at their sexual intercourse. Especially, Amyl nitrite, Methamphetamine, 5-methoxy-N, N-diisopropyltryptamine (5-MeO-DIPT; Foxy), and 3, 4-methylenedioxy- methamphetamine (MDMA; Ecstasy) are used, and they sometimes cause the physical and mental disorders. However, the actual drug inducing troubles among Japanese HIV-infected drug users had not yet been discussed enough. In this report, we describe three cases with HIV infection; a case developed severe neuroleptic malignant syndrome (NMS) after taking 5-MeO-DIPT, a case with persistent convulsion due to multiple drug intake and a case with rhabdomyolysis due to the non-subjective methamphetamine intake. Through these cases, we raise and discuss several underlying problems associated with drug use among HIV-infected individuals.

Drug's Cost Can Determine Availability, Court Says

Back to table of contents Previous article Next article Professional NewsFull AccessDrug's Cost Can Determine Availability, Court SaysJun YanJun YanSearch for more papers by this authorPublished Online:7 Sep 2007https://doi.org/10.1176/pn.42.17.0007The maker of donepezil (Aricept), a medication used in the treatment of Alzheimer's disease, challenged the National Institute for Health and Clinical Excellence (NICE), which advises the state-run health systems in England and Wales on drug coverage, in court over the institute's restrictions on the product.The court upheld the national agency's power to restrict insurance coverage of medications based on assessments of their cost-effectiveness.The Japanese drug manufacturer Eisai, which shares the worldwide marketing of donepezil with Pfizer, brought a legal challenge against NICE over its guidance document that limits the use of the drug. In the guidance document, dated November 2006, NICE stated that the use of donepezil in patients with mild Alzheimer's was not cost-effective and thus recommended that the National Health Service (NHS) pay for the treatment for patients with Alzheimer's disease of moderate severity only (that is, those with a Mini-Mental State Examination score of between 10 to 20 points).NICE, which was established in 1999, is responsible for systematic review of the safety, efficacy, and cost-effectiveness of drugs and medical devices. It provides guidance to the NHS in determining coverage for drugs and medical products. It is the cost-effectiveness assessment and recommendations that have sparked the dispute.Eisai filed the lawsuit with support from Pfizer and the Alzheimer's Society, a patient-advocacy group. It argues that NICE's analyses underestimate the drug's benefits, especially the benefits for care-givers of Alzheimer's patients, and that the health-economics models used by NICE are flawed. This is the first time it has faced judicial review of its decisions.In a ruling handed down on August 10, the judge affirmed that NICE can restrict access to medicines and rejected the plaintiffs' claims. It also ruled, however, that NICE had breached its duties by not offering specific guidance in testing the disease severity of patients with learning disabilities and those for whom English is not their first language, which might unfairly deny appropriate treatment for these patients.The court's decision has direct implications for NHS coverage of two other Alzheimer's drugs, rivastigmine and galantamine, which are also restricted to use in patient with moderate Alzheimer's disease as recommended by the NICE guidelines. All three drugs are in the class of reversible anticholinesterase inhibitors. They have been shown to improve the symptoms of Alzheimer's disease, but there is no evidence to indicate that they reverse the course of the underlying dementia process, according to the labeling information approved by the U.S. Food and Drug Administration.The case attracted international attention, because it could set a precedent for others to challenge government attempts to restrict or deny payment for medical treatments based on the economic “worth” of a drug's efficacy. The state-run health care systems in the United Kingdom have sought to stem the rapid growth of medical expenditure through NICE-recommended restrictions, an approach that other countries' national health systems are watching closely.The pharmaceutical industry is increasingly seeking to stop government payers' cost-cutting efforts aimed at reducing health care spending. The Association of the British Pharmaceutical Industry has announced plans to challenge the legality of another NHS policy related to switching patients from brand-name drugs to cheaper generic substitutions, as reported by Reuters on July 4. In addition, the July 13 Wall Street Journal reported on a campaign in the United States by makers of epilepsy drugs to pass legislation making it more difficult to switch epilepsy patients to generic drugs.The NICE guidance on Alzheimer's disease treatment is posted at<http://guidance.nice.org.uk/TA111/guidance/pdf/English>.▪ ISSUES NewArchived

Clinical Research in Japan: ways to Alleviate Unnecessary Regulatory Burdens

Resumo For drug discovery and development today, synergy between pure science, clinical research, and the organization of clinical trials is essential. In Japan, there is a delay in the institutional response to this need. This paper identifies one of the bottlenecks in the Japanese regulatory process. Clinical research undertaken by university researchers and medical doctors are not integrated into the Japanese drug approval procedure. Therefore, their efforts and research data are wasted in the inherently unpredictable nature of long and costly biomedical research. Collaborative efforts between companies and researchers/medical doctors should be encouraged through institutional incentives, by integrating university and medical clinical research ab initio into regulatory process. In order to achieve this, it would be necessary to promote commercial exchange of database information and short-term employment of researchers in those projects leading to regulatory approval.

Pesquisa clínica no Japão: caminhos para aliviar cargas regulatórias desnecessárias

Para a descoberta e desenvolvimento de medicamentos hoje, a sinergia entre ciência pura, pesquisa clínica e planejamento de testes clínicos é essencial. No Japão, a resposta a essa necessidade foi adiada. Este artigo identifica um dos gargalos no processo regulatório japonês. A pesquisa clínica sob responsabilidade dos pesquisadores da universidade e dos médicos não está integrada aos procedimentos de aprovação dos medicamentos japoneses. Portanto, seus esforços e dados de pesquisas são dissipados na longa e dispendiosa pesquisa biomédica, de natureza inerentemente imprevisível. Esforços colaborativos entre empresas e médicos/pesquisadores deveriam ser estimulados por meio de incentivos institucionais, integrando a universidade e a pesquisa clínica ab initio ao processo regulatório. Para conseguir isso, seria necessário promover o intercâmbio comercial de informações de bancos de dados e, a curto prazo, o emprego de pesquisadores nos projetos que levam à aprovação regulatória.

Genetic Variations and Haplotype Structures of the ABC Transporter Gene ABCC1 in a Japanese Population

Multidrug resistance-related protein 1 (MRP1), an ATP-binding cassette transporter encoded by the ABCC1 gene, is expressed in many tissues, and functions as an efflux transporter for glutathione-, glucuronate- and sulfate-conjugates as well as unconjugated substrates. In this study, the 31 exons and their flanking introns of ABCC1 were comprehensively screened for genetic variations in 153 Japanese subjects to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of ABCC1 that is necessary for pharmacogenetic studies of the substrate drugs. Eighty-six genetic variations including 31 novel ones were found: 1 in the 5'-flanking region, 1 in the 5'-untranslated region (UTR), 20 in the coding exons (9 synonymous and 11 nonsynonymous variations), 4 in the 3'-UTR, and 60 in the introns. Of these, eight novel nonsynonymous variations, 726G>T (Trp242Cys), 1199T>C (Ile400Thr), 1967G>C (Ser656Thr), 2530G>A (Gly844Ser), 3490G>A (Val1164Ile), 3550G>A (Glu1184Lys), 3901C>T (Arg1301Cys), and 4502A>G (Asp1501Gly), were detected with an allele frequency of 0.003. Based on the LD profiles, the analyzed regions of the gene were divided into five LD blocks (Blocks -1 and 1 to 4). The multiallelic repeat polymorphism in the 5'-UTR was defined as Block -1. For Blocks 1, 2, 3 and 4, 32, 23, 23 and 13 haplotypes were inferred, and 9, 7, 7 and 6 haplotypes commonly found on > or = 10 chromosomes accounted for > or = 91% of the inferred haplotypes in each block. Haplotype-tagging single nucleotide polymorphisms for each block were identified to capture the common haplotypes. This study would provide fundamental and useful information for the pharmacogenetic studies of MRP1-dependently effluxed drugs in Japanese.

Genetic Variations of the ABC Transporter Gene ABCC3 in a Japanese Population

An ATP-binding cassette transporter, multidrug resistance-related protein 3 (MRP3), is encoded by the ABCC3 gene. The MRP3 protein is expressed in several tissues, and functions as an efflux transporter for conjugated as well as unconjugated substrates. In this study, the 31 ABCC3 exons and their flanking introns were comprehensively screened for genetic variations in 89 Japanese subjects. Forty-six genetic variations, including 21 novel ones, were found: 8 were located in the 5'-flanking region, 14 in the coding exons (8 synonymous and 6 nonsynonymous variations), and 24 in the introns. Of these 46 variations, five novel nonsynonymous variations, 2221C>T (Gln741Stop), 2395G>A (Val799Met), 2798_2799delAG (Gln933ArgfsX64), 3657C>A (Ser1219Arg), and 4217C>T (Thr1406Met), were found as heterozygous variations. The allele frequencies were 0.011 for Ser1219Arg and 0.006 for the other four variations. Gln741Stop induces a stop codon at codon 741. Gln933ArgfsX64 causes a frame-shift at codon 933, resulting in early termination at codon 997. Both variations result in loss of 6 transmembrane helices (from the 12th to 17th helices) in the C-terminus and all regions of nucleotide binding domain 2. Thus, both variant proteins are assumed to be inactive. These data provide fundamental and useful information for pharmacogenetic studies on MRP3-transported drugs in Japanese.

Genetic Variations and Frequencies of Major Haplotypes in SLCO1B1 Encoding the Transporter OATP1B1 in Japanese Subjects: SLCO1B1*17 is More Prevalent Than *15

A liver-specific transporter organic anion transporting polypeptide 1B1 (OATP1B1, also known as OATP-C) is encoded by SLCO1B1 and mediates uptake of various endogenous and exogenous compounds from blood into hepatocytes. In this study, 15 SLCO1B1 exons (including non-coding exon 1) and their flanking introns were comprehensively screened for genetic variations in 177 Japanese subjects. Sixty-two genetic variations, including 28 novel ones, were found: 7 in the 5'-flanking region, 1 in the 5'-untranslated region (UTR), 13 in the coding exons (9 nonsynonymous and 4 synonymous variations), 5 in the 3'-UTR, and 36 in the introns. Five novel nonsynonymous variations, 311T>A (Met104Lys), 509T>C (Met170Thr), 601A>G (Lys201Glu), 1553C>T (Ser518Leu), and 1738C>T (Arg580Stop), were found as heterozygotes. The allele frequencies were 0.008 for 1738C>T (Arg580Stop) and 0.003 for the four other variations. Arg580Stop having a stop codon at codon 580 results in loss of half of transmembrane domain (TMD) 11, TMD12, and a cytoplasmic tail, which might affect transport activity. In addition, novel variations, IVS12-1G>T at the splice acceptor site and -3A>C in the Kozak motif, were detected at 0.003 and 0.014 frequencies, respectively. Haplotype analysis using -11187G>A, -3A>C, IVS12-1G>T and 9 nonsynonymous variations revealed that the haplotype frequencies for (*)1b, (*)5, (*)15, and (*)17 were 0.469, 0.000 (not detected), 0.037, and 0.133, respectively. These data would provide fundamental and useful information for pharmacogenetic studies on OATP1B1-transported drugs in Japanese.

Authentication and Chemical Study of Isodonis Herba and Isodonis Extracts

Isodonis Herba is used as a Japanese dietary supplement and folk medicine. The extract of the herb (Isodonis extract) is also used as a food additive whose major compound is enmein (1). Here we compared internal transcribed spacer sequences of nuclear ribosomal DNA from Isodonis Herba available on the Japanese and Chinese crude drug markets, and found that the former derived from Isodon japonicus and Isodon trichocarpus, while the latter derived from distinct species such as Isodon eriocalyx. The liquid chromatography/mass spectrometry profiles of Isodonis Herba were classified into four chemotypes (A to D) according to the ratio of the major constituents. Types B and C contained 1 and oridonin (2) as major components, respectively. An intermediate (or mixed) form of types B and C in various ratios was designed type A. Type D contained eriocalyxin B (3) as its major component. Japanese herba were types A-C, while Chinese herba were types C and D. The commercial Isodonis extract products tested were classified as type D, suggesting that they originated from Chinese Herba. Understanding the relationship between extract constituents and DNA profiles is important for the official specification of dietary supplements and food additives of plant origin.

Development and validation of the Stimulant Relapse Risk Scale for drug abusers in Japan

Objective To develop and validate a multidimensional measure of relapse risk for stimulants in Japanese drug abusers. Methods A Stimulant Relapse Risk Scale (SRRS) was developed based on the Marijuana Craving Questionnaire and a discussion among three psychiatrists. We created 48 items after confirming the items including a variety of relapse risk, such as craving (expectancy, compulsivity, etc.) and emotionality problems. One hundred inpatients and outpatients with a history of stimulant abuse (71 males and 29 females) were recruited with informed consent, and were administered the SRRS. The Visual Analogue Scale for drug craving (VAS), Addiction Severity Index for Japanese (ASI-J), and data on relapse within 3 and 6 months after the rating were used for the validation. Results Exploratory factor analysis highlighted five factors: anxiety and intention to use drug (AI), emotionality problems (EP), compulsivity for drug use (CD), positive expectancies and lack of control over drug (PL), and lack of negative expectancy for drug use (NE). These accounted for 48.3% of the total variance. Thirty of the 43 items were classified into the five subscales. Cronbach's alpha coefficient for each subscale ranged from .55 to .82, and was .86 for the total SRRS, indicating their adequate internal consistency. AI, CD, PL, and total SRRS were significantly correlated with the drug-use composite score of the ASI-J, supporting their concurrent validity. AI, PL, NE, and total SRRS were significantly correlated with relapse, implying their predictive validity. Conclusions The SRRS has multidimensional psychometric properties useful for assessing the various aspects of stimulant relapse risk.

Four novel defective alleles and comprehensive haplotype analysis of CYP2C9 in Japanese

Genetic variations in cytochrome P450 2C9 (CYP2C9) are known to contribute to interindividual and interethnic variability in response to clinical drugs such as warfarin. In the present study, CYP2C9 from 263 Japanese subjects was resequenced, resulting in the discovery of 62 variations including 32 novel ones. In addition to the two known non-synonymous single nucleotide polymorphisms (SNPs), Ile359Leu (*3; allele frequency=0.030) and Leu90Pro (*13; 0.002), seven novel non-synonymous SNPs, Leu17Ile (0.002), Lys118ArgfsX9 (*25; 0.002), Thr130Arg (*26; 0.002), Arg150Leu (*27; 0.004), Gln214Leu (*28; 0.002), Pro279Thr (*29; 0.002) and Ala477Thr (*30; 0.002), were found. Functional characterization of novel alleles using a mammalian cell expression system in vitro revealed that *25 was a null allele and that *26, *28 and *30 were defective alleles. The *26 product showed a 90% decrease in the Vmax value but little change in the Km value towards diclofenac. Both *28 and *30 products showed two-fold higher Km values and three-fold lower Vmax values than the *1 allele, suggesting the importance of Gln214 and Ala477 for substrate recognition. Linkage disequilibrium and haplotype analyses were performed using the detected variations. Only five haplotypes (frequency >0.02) accounted for most (>87%) of the inferred haplotypes, and they were closely associated with the haplotypes of CYP2C19 in Japanese. Although the haplotype structure of CYP2C9 was rather simple in Japanese, the haplotype distribution was quite different from those previously reported in Caucasians and Africans. Taken together, novel defective alleles and detailed haplotype structures would be useful for determining metabolic phenotypes of CYP2C9 substrate drugs in Japanese and probably Asians.

Prediction of in vivo drug clearance from in vitro data. II: Potential inter-ethnic differences

Potential differences in drug clearance between Japanese and Caucasians were investigated by integrating data on demography, liver size, the abundance of the major cytochromes P450 and in vitro metabolic parameters. Eleven drugs (alprazolam, caffeine, chlorzoxazone, cyclosporine, midazolam, omeprazole, sildenafil, tolbutamide, triazolam, S-warfarin and zolpidem) fulfilled the entry criteria of the study (i.e. the necessary in vitro metabolism data were available and clearance values had been reported both in Caucasians and Japanese). Values of relevant biological variables were obtained from the literature, and clearance predictions were made using the Simcyp® Population-Based ADME Simulator. The ratios of observed oral clearance (CLp.o.) values in Caucasians compared with Japanese ranged from 0.6 to 2.8 (integrating data from 82 sources). The CLp.o. values for alprazolam, caffeine and zolpidem were not statistically different between Caucasian and Japanese (p > 0.05), whereas those for chorzoxazone, cyclosporine, omeprazole, tolbutamide and triazolam were higher in Caucasians (p < 0.05), and those for midazolam, sildenafil and S-warfarin were higher in Japanese (p < 0.05). CLp.o. values, predicted from in vitro data, were within 3-fold of observed in vivo values for seven of the 11 drugs in Japanese. Values for the predicted ratios ranged from 1.6 to 4.9. The predicted ratios were not significantly different from observed ratios for cyclosporine, omeprazole, tolbutamide and triazolam. Only partial success in predicting ethnic differences in clearance indicates the need for larger and more reliable databases on relevant variables. With such information, in silico predictions might be used with more confidence to decrease the need for repeating pharmacokinetic studies in different ethnic groups.

The Determinants of Pharmaceutical R&amp;D Expenditures: Evidence from Japan

During the past 20 years, the world pharmaceutical industry has experienced a dramatic increase in R&D intensity. We apply and extend a model developed by Grabowski and Vernon (2000, Journal of Evolutionary Economics, 10, 201–215) with a pooled data sample of the 15 publicly listed Japanese drug firms for the period 1987–1998. As in the original study, we find expected returns to be an important determinant of R&D spending in the Japanese drug industry, albeit considerably smaller than in the U.S., which is particularly obvious in the case of returns from newly introduced drugs. However, our results are sensitive to econometric model specification, in particular to controlling for serial correlation and to a dynamic specification of the baseline model. Likewise, estimates on financial constraints are sensitive to model specification, indicating that Japanese drug firms face small or no financial constraints. Our results are consistent with the general literature on R&D investment behaviour, yet raise some methodological questions with regard to the original study.

抗菌剤感受性試験結果の解釈と投与方法の問題点

In the treatment of infectious diseases, the antimicrobial susceptibility test is an important laboratory test in the selection of appropriate antimicrobial agents. In most hospitals, the antimicrobial susceptibility test is carried out by the method stipulated by NCCLS (National Committee for Clinical Laboratory Standards), a U.S. organization, and thus the standard (break point) used for interpreting the result is based on dosage regimens in that country. In the present study, we calculated time above MIC (T >MIC) for the dosage regimen indicated by Japanese drug packages inserts for ceftazidime (CAZ) and piperacillin (PIPC). T >MIC is a PK/PD parameter related to the effect of beta-lactams and is calculated using Japanese serum concentration measurement data for them. We determined that this parameter covered the full range judged by the susceptibility test to be sensitive (S) and concluded that, based on T >MIC, sufficient efficacy might not be achieved under the Japanese dosage regimen even though the result had been S in the susceptibility test. This is because there are many differences in dosage regimens between Japan and the U.S.Despite the fact that Japan has its own dosage regimens, the break point used is the one in NCCLS, which is based on dosage regimens in the U.S., and thus the results of susceptibility tests in Japan may cause susceptibility to be overestimated.

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

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. 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). (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. 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.

Fibrinogen-Depleting Agents for Acute Ischemic Stroke

Fibrinogen-depleting agents reduce fibrinogen in blood plasma, reduce blood viscosity and hence increase blood flow. This may help remove any occluding thrombus and reestablish blood flow to the affected area of the brain after an ischemic stroke. The risk of hemorrhage may be less than with thrombolytic agents. The objective of this review was to assess the effect of fibrinogen-depleting agents in patients with acute ischemic stroke. We searched the Cochrane Stroke Group Trials Register (last searched May 2003). In addition, we searched the following electronic databases: EMBASE (1980 to October 2001), China Biological Medicine Database (CBM-disc, 1981 to December 2002), Chinese Stroke …

Are we all global now? Local vs. foreign sources of corporate competence: the case of the Japanese pharmaceutical industry

AbstractThis study links the highly distinctive national contexts of the pharmaceutical industry to the evolution of innovative capabilities for Japanese drug firms from 1975 to 1995. During these two decades, the Japanese domestic environment for pharmaceuticals changed radically, encouraging a ‘bubble’ of trivial innovations. Experience by Japanese firms in their domestic market predominantly determined their innovative capabilities, pushing these firms towards trivial innovation. Corporate experience in the socially ‘proximate’ markets of Southern Europe served as a strategic complement for significant innovation by Japanese drug firms, and thus as a partial counterweight to the home market. Unfortunately, corporate diversification was a strategic substitute for significant innovation, and many Japanese drug firms are significantly diversified. The resulting degradation of innovative capability for Japanese drug firms has locked most of them into an increasingly unattractive home market. Copyright © 2004 John Wiley &amp; Sons, Ltd.

Utilisation of Foreign Clinical Data in Japanese New Drug Approval Review

Objective: Foreign clinical evidence for efficacy and safety of new pharmaceutical drugs was utilised in decisions for marketing approval in Japan without specific regulatory guidelines until a new internationally harmonised guidance for bridging strategy was introduced in 1998. We examined how foreign clinical studies were used in recent marketing approval decisions and also how the new guidelines affected the trends of foreign data acceptance.

Utilisation of Foreign Clinical Data in Japanese New Drug Approval Review

Objective: Foreign clinical evidence for efficacy and safety of new pharmaceutical drugs was utilised in decisions for marketing approval in Japan without specific regulatory guidelines until a new internationally harmonised guidance for bridging strategy was introduced in 1998. We examined how foreign clinical studies were used in recent marketing approval decisions and also how the new guidelines affected the trends of foreign data acceptance. Methods: New drug applications (NDAs) approved between 1999 and 2003 with review reports issued by the regulatory authority available on the official website were scrutinised. Focusing on critical clinical trials including dose response studies in phase II and confirmatory studies in phase III, we classified the type of utilisation of foreign clinical data into several groups. Results: Of the 171 NDAs approved during this period, 55 (32%) contained foreign studies as formally submitted data. Twenty NDAs (12%) were approved based on the bridging strategy. In 24 NDAs (14%) important foreign data were used as references, but not as formally submitted materials. NDAs that were given orphan drug status or priority review status were more likely to be submitted and approved on the basis of foreign clinical data. The number of bridging-based NDAs successfully approved increased from three in 2000 to ten in 2002, although confusion about the application of the new guidelines was observed after the guidelines’