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Welcome Address Drug review procedures and drug development strategies are changing rapidly as a result of the “The International Conference on Harmonization of Technical Requirements for the Registration of Pharmaceuticals for Human Use” (ICH). In particular, the E5 guideline, issued in August, 1998, enable the extrapolation of Western clinical data to new regions of the world. In addition, the availability of pharmacogenomic information is likely to play a prominent role in future new drug development, especially as regards individualized or tailor-made medicine. The two concepts can lead to profound effect of drug development programs worldwide. It is therefore very important to create a forum for discussing the multiple issues surrounding these concepts. This symposium – the 3rd Kitasato University – Harvard School of Public Health Symposium on Advancing Global Drug Development Techniques: Simultaneous Worldwide Development and Pharmacogenomics – is partially a result of partnership formed in 2000 between the Department of Biostatistics at Kitasato University Graduate School and Harvard School of Public Health. The symposium will address a variety of topics related to bridging and worldwide development strategies and pharmacogenomics, including simultaneous, worldwide development strategies (overview, the new challenges, practical implementation of ICH-E5 2002 guidelines, and APEC report and the symposium discussion), pharmacogenomics, and implementation of global development program. We have organized the sessions so as to have both the Western and Eastern perspectives. It is our great pleasure to welcome you to this important meeting. Stephen W. Lagakos, Ph.D. Harvard School of Public Health

Masahiro Takeuchi, Sc.D. Kitasato University Graduate School The Kitasato Institute

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PROGRAM Wednesday, October 2, 2002 12:00-13:00 Registration 13:00-13:20 Opening remarks and welcoming address

Toshiro Sato Kitasato University Declan P. Doogan Pfizer Inc.

13:20-13:30 Congratulatory remarks Yoshikazu Hayashi Ministry of Health, Labour and Welfare

SESSION1: SIMULTANEOUS/WORLDWIDE DEVELOPMENT STRATEGIES: OVERVIEW

Session Chairperson: Yoshio Yazaki International Medical Center of Japan

13:30-14:00 Several years experience on bridging studies and the future Yasuhiro Fujiwara National Cancer Center Hospital

CLINICAL UPDATE IN ASIA: 14:00-14:20 Evaluation of ethnic sensitivity in Taiwan and the related issues of

statistical consideration Chien-Hua Wu Center for Drug Evaluation, Taiwan, National Taipei University

14:20-14:40 Experience in Korea on bridging studies In-Jin Jang Seoul National University

14:40-15:20 How does difference in medical practice in Japan and the rest of the world effect drug development? Anil K. Malhotra Albert Einstein College of Medicine Mitsukuni Murasaki --- Via TV Institute of CNS Pharmacology Jun Ishigooka --- Via TV Kitasato University

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15:20-16:00 Panel discussion ---What are the keys for bridging and what made us fail in bridging? ---What is required to use Asian data for the NDA filing in Japan? Panelists: The above speakers plus Yoshikazu Hayashi Ministry of Health, Labour and Welfare Masuhiro Kato AstraZeneca K.K. Thomas Kuerner Nippon Boehringer Ingelheim Co., Ltd.

16:00-16:15 Coffee Break SESSION2: SIMULTANEOUS/WORLDWIDE DEVELOPMENT STRATEGIES: NEW

CHALLENGIES Session Chairperson: Hiroo Imura Council for Science and Technology Policy, Cabinet Office

16:15-16:35 New approaches of dose range finding Yusuke Tanigawara Keio University, School of Medicine

16:35-16:55 Role of surrogate markers in psychiatry Noriyoshi Takei Hamamatsu University School of Medicine

16:55-17:15 The search for alternatives to randomised comparative studies Peter Boyle European Institute of Oncology

17:15-18:05 Panel discussion Panelists: The above speakers plus Tsutae Nagata GlaxoSmithKline K.K. Katsuyoshi Shimatani Pfizer Pharmaceuticals Inc.

18:20-20:30 Reception

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Thursday, October 3, 2002 8:00-8:30 Registration SESSION3: SIMULTANEOUS/WORLDWIDE DEVELOPMENT STRATEGIES: ICH-E5

Session Chairperson: Stephen W. Lagakos Harvard School of Public Health

8:30-9:00 Update and progress: Report from the meetings of Feb in Brussels and Sep in Washington DC Robert T. O'Neill --- Via TV US Food and Drug Administration

9:00-9:20 Use of foreign data for drug approval Ann T. Farrell --- Via TV US Food and Drug Administration

9:20-10:00 Panel discussion Caroline N. Loew --- Slide presentation Pharmaceutical Research and Manufacturers of America Panelists: Michael J. Ferris Aventis Pharma Ltd. Eric W. Lewis GlaxoSmithKline K.K. Shunsuke Ono Kanazawa University

10:00-10:20 Coffee Break SESSION4: MORE CONCRETE PLAN AND ACTIONS BASED ON ICH AGREEMENT,

APEC REPORT AND TODAY'S DISCUSSION Session Chairperson: Masahiro Takeuchi Kitasato University Graduate School, The Kitasato Institute

10:20-10:50 Genetics as a means of understanding intrinsic ethnic differences – genetic variation on metabolism/transporter/receptor Junichi Azuma Osaka University

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10:50-12:00 Workshop: Short summary and action plan aiming at simultaneous worldwide development --- Definition of simultaneous development and Asian studies --- Categorization of issues as strategies and operation --- Agreement --- Action --- Direction Chaired by Stephen Lagakos and Masahiro Takeuchi Panelists: Masaru Iwasaki Aventis Pharma Ltd. Kihito Takahashi Banyu Pharmaceutical Co., Ltd. Andrew J. Wood Eli Lilly Japan K.K.

12:00-13:00 Lunch SESSION5: PHARMACOGENOMICS: DRUG DISCOVERY AND DRUG DEVELOPMENT

BASED ON THE GENETIC ANALYSIS Session Chairperson: Tetsuya Kamataki Hokkaido University

13:00-13:20 New monoclonal antibody approved for advanced breast cancer: Trastuzumab Shin-ichi Nihira Chugai Pharmaceutical K.K.

13:20-13:40 The human approach to target validation and drug discovery – genomic and integrated technology approach on respiratory, GI, cardiovascular, inflammatory disease Alastair J. Riddell Pharmagene Plc

13:40-14:00 From genomics to drugs – gene haplotypes and drug response – Kevin Rakin Genaissance Pharmaceuticals, Inc.

14:00-14:20 Toxicogenomics in the USA – molecular toxicological approach in drug discoverty and development – Ikuo Horii Pfizer pharmaceuticals Inc.

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14:20-14:40 Regenerative medicine

Yoshiki Sasai Kyoto University

14:40-15:10 Panel discussion ---What differences do we have between Japan and the West? (eg. res. trend, system, policy, regulatory / clinical environment, public acceptance, venture business, national support etc.) Panelists: The above speakers plus Hiroshi Gushima Yamanouchi Pharmaceutical Co., Ltd., Biofrontier Partners, Inc.

15:10-15:30 Coffee Break SESSION6: IMPLEMENTATION OF GLOBAL DEVELOPMENT PROGRAMS

Session Chairperson: Declan P. Doogan Pfizer Inc.

15:30-15:50 Drug development in Asia – an industry perspective – Stephen Uden Pfizer Pharmaceuticals Inc.

15:50-16:10 Lessons learned from a global clinical trial --- an experience of ‘RENAAL’ study Kiyoshi Kurokawa Tokai University

16:10-16:30 Experience of a Japan /Korea regional trial Henk J. de Koning Gans Pharmacia K.K.

16:30-16:50 Summary and conclusion

Stephen W. Lagakos Harvard School of Public Health

16:50-17:00 Closing remarks Masahiro Takeuchi Kitasato University Graduate School, The Kitasato Institute

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SESSION1

Several Years Experience on Bridging Studies and the Future

Yasuhiro Fujiwara Breast and Medical Oncology Group, National Cancer Center Hospital, Japan As of September 1, 2002, following implementation of the ICH-E5 guidance in 1998, eleven drugs (fexofenadine, approved September 22, 2000; oseltamivir, approved December 12, 2000; anastrozole, approved December 22, 2000; sumatriptan, approved June 20, 2001; zolmitriptan, approved June 20, 2001); palivizumab, approved January 17, 2002; oseltamivir dry-syrup, approved January 17, 2002 ; 4 other drugs, of which the PMDEC (Pharmaceuticals and Medical Devices Evaluation Center; “so-called Japanese FDA”)’s review reports are not yet open to public) have been approved with a prospectively conceptualized bridging strategy during clinical development. As to the contents of these bridging studies, randomized, fixed dose, placebo-controlled, dose-response study was most popular form of the study. The most important, but difficult to solve, discussion point in the review process was how to explain (or bridge) the difference in medical practice between Japan and the foreign countries; i.e. extrinsic factors. Furthermore, problems other than clinical trial results (lack of knowledge about Japanese medical practice; bureaucractic sponsor’s decision making process; wrong translation of NDA documents (especially clinical section)) disturbed smooth review. I will briefly overview and comment on these topics based on publicly available review reports (in Japanese) from the Internet (http://www.pharamasys.gr.jp/shinyaku/ index.html).

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SESSION1

Evaluation of Ethnic Sensitivity in Taiwan and the Related Issues of Statistical Consideration

Chien-Hua Wu Centre for Drug Evaluation, National Taipei University, Taiwan Lin et. al. (2002) published a paper entitled “Assessment of the extrapolation of foreign clinical data for registration purposes” in Drug Information Journal showed that eight out of 20 cases had the ethnic concern between original country and Taiwan in year 2001. In those eight cases, seven of them considered to be a safety issue, and the last case is due to lack of data to support the drug effectiveness in the general population. Eventually, the evaluation system in Taiwan borrows the ICH guideline coupling with safety consideration to judge the ethnic sensitivity. It seems like it is not easy to tell the direction of the drug effectiveness in a different population based upon the evaluation items. According to ICH E5, PK profile is introduced to predict the PD profile in local country, but it is not applicable if the correlation between PK profile and PD profile in the original population does not exist. The purpose of this presentation introduces two statistical issues on bridging study. That is how to detect the ethnic sensitivity and how to conduct the clinical trial in a small population like Taiwan if there is an ethnic concern. Conducting a multinational trial or executing 40 evaluable patients using Bayesian approach in the local country is recommended to detect the ethnic sensitivity if the relationship between PK and PD is not able classified. Otherwise, the evaluation process based upon ICH E5 is introduced. If the ethnic difference has been proven, a small sample size with the same power as conventional method is recommended to show the drug effectiveness in Taiwan (Wu et .al., 2001).

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SESSION1

Experience in Korea on Bridging Studies

In-Jin Jang Seoul National University, College of Medicine, Korea The drug regulatory system in Korea is changing a lot. Korean Food and Drug Administration (KFDA) is implementing IND system these days. ‘Conditional approval of product for clinical trial’, ‘approval system by protocol’ and ‘approval system by study phase’ had been discarded. Pre-IND Meeting and flexible regulation on manufacturing/importing of clinical supplies are made possible. For the approval of drugs developed in foreign countries, KFDA adopted bridging concept of ICH E5 in Dec 1999. From July 2001, all the NDA should be compliant to bridging concept, that is the sponsor should submit a request for waver for bridging data on the basis of ethnic insensitivity of ICH E5 or submit NDA package with at least one clinical trial data intended for bridging. Now under the IND system, the sponsor can do practically any clinical trial in Korea to generate bridging data. Until now, more than 8 products were waived of any local clinical data on the basis of bridging concept. Four of them belonged to orphan drug category, one was diagnostic, one was topical, and one was drug for life threatening disease. Among them one antibiotic was waived of clinical data on the basis of ethnic insensitivity and in vitro microbiological sensitivity test of local clinical isolates. Three products were approved with single clinical trial data. All of them were pharmacokinetic (PK) studies and one was done in other country. Currently, 3 more sponsors finished PK studies and preparing for study report and/or bridging study exemption request. More than 4 sponsors are planning to do PK based bridging data generation and submitted clinical trial protocol. Currently more than 12 local clinical trials are underway for bridging data generation as phase 3 design in Korea. Korean investigators are participating in more than 24 multinational phase 3 and phase 2 (2 trials of the 24) trials. KFDA is expecting many of the 24 multinational trial data will be submitted as a bridging data in the future. Until now only four products have been approved under the genuine bridging concept of ICH E5. But many new drugs will be approved in the very near future as such. For there are many clinical trials undergoing to generate bridging data. One interesting finding is that there are no dose-finding or dose-response studies done or planned in Korea for bridging data generation.

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SESSION1

How Does Difference in Medical Practice in Japan and the Rest of the World Effect Drug Development?

Pharmacogenomics in Psychiatry: Implications for New Drug Development

Anil K. Malhotra The Zucker Hillside Hospital, Albert Einstein College of Medicine, USA Pharmacogenomic strategies are increasingly being utilized to identify biological predictors of response to psychotropic medications. To date, most studies have been conducted focusing on the antidepressant and antipsychotic medications. Initial data in this regard, however, have been inconsistent, perhaps secondary to relatively small sample sizes, the use of retrospective, non-specific assessments of outcome, and the fact that allele frequencies may markedly differ between ethnic groups. Moreover, these initial studies have only included a limited number of single nucleotide polymorphisms (SNPs) – primarily due to the paucity of data on genetic variation and limitations in genotyping capabilities. Over the past two years, the dramatic increase in genomic information and concomitant improvements in molecular technology have provided the means to markedly enhance pharmacogenetic studies. For example, complete sequence data is now available for more than 10,000 genes, and over 5,000,000 SNPs have been identified throughout the genome. Moreover, advances in molecular technology have markedly reduced the expense of genotyping. These developments, coupled with new statistical genetic approaches and the introduction of routine DNA collection into large-scale clinical trials, suggest that comprehensive whole genome association studies of psychotropic drug response are now feasible to consider. In this presentation, we will review the first generation of genetic studies of psychotropic drug response, examine the new developments in pharmacogenomics, and discuss strategies for utilizing pharmacogenomic techniques in new drug development in psychiatry.

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SESSION1

How Does Difference in Medical Practice in Japan and the Rest of the World Effect Drug Development?

Mitsukuni Murasaki Institute of CNS Pharmacology, Japan The greatest difference in the development of psychotoropics between Japan and the Western countries is that a placebo cannot be used in clinical trials for antipsychotic drugs and antidepressants in Japan. Regarding antipshychotic drugs, there is a body of evidence demonstrating that early detection and treatment of schizophrenia determines the prognosis of the disease. In light of this evidence, it is impermissible to use a placebo, which is most likely to worsen the prognosis. Patients with acute-phase psychotic symptoms are enrolled in Western trials, while chronic-phase patients with negative symptoms are included in Japanese trials. This may explain why bridging studies are not feasible. In clinical trails for antidepressants, a placebo cannot be used during the phase of acute treatment. Placebo-controlled studies are beginning to be employed in relapse prevention studies, which are required in Europe. What is the validity of a study in which relapse is awaited? There is a consensus that pharmacotherapy should be continued for at least 6 months for the first episode and for lifetime from the next episode. Wouldn't it be too hard for the patients to wait for relapse to occur even in trial settings?

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SESSION2

New Approaches of Dose Range Finding

Yusuke Tanigawara Department of Pharmacy, Keio University Hospital, Japan A greater deal of attention has been given to the internationally harmonized drug development among the ICH regions (U.S.A., EU and Japan) in order to avoid redundant trials and to save time and cost. The concept of “bridging study” and “global study” were proposed as new challenges to drug development. An obvious benefit of these concepts includes the extrapolation of the foreign clinical data, e.g. comparative confirmatory studies, long-term administration studies and studies on special populations, to the new region. In a complete clinical data package based upon the bridging concept, it is essential to provide a scientific rationale that the dosage and dose regimen established in foreign region is applicable to the new region. Because the package skips local therapeutic confirmatory studies, the bridging components have to include pharmacokinetics, pharmacodynamics or dose-response, and supplemental clinical data on efficacy and safety in the new region. The dose-response relationship is particularly important to demonstrate the validity of proposed dose and dosage regimen. A mechanistic framework to describe the dose-response relationship is the pharmacokinetic and pharmacodynamic approach. Pharmacokinetics (PK) describes the relationships between dose/dosage regimen and drug concentration-time profiles in the body. On the other hand, pharmacodynamics (PD) describes drug exposure to the body versus response relationships. There are many factors that can cause variability in drug response, which include the genetic, physiological, pathological, and environmental factors. Some of these factors alter pharmacokinetics whereas some of them affect pharmacodynamics. The population PK is especially useful to describe the pharmacokinetic characteristics in patients. This is a feasible method implemented in a clinical situation because it depends upon a mixed effect modeling using sparsely sampled drug concentration data. Furthermore, simultaneous measurement of drug concentrations and pharmacological endpoints leads to PK/PD relation analysis. Recently, there are many applications of the PK/PD approach in drug development, which include a variety of therapeutic fields such as hypertension, allergy, diabetics, oncology, infectious diseases, and so on. The present talk provides the fundamental idea and implementation of the population-based PK/PD approach into the drug development program.

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SESSION2

Role of Surrogate Markers in Psychiatry

Noriyoshi Takei Department of Psychiatry and Neurology and Staley Foundation (US) Research Center in Japan, Hamamatsu University School of Medicine, Japan Positron emission tomography (PET) is a useful tool to in vivo investigate cerebral metabolic rate and to measure the binding potential of various neurotransmitters in the human brain. It is firmly believed that a disturbed dopaminergic system is involved in the formation of psychotic symptoms, in particular in schizophrenia. Based on our recent PET study of patients with methamphetamine psychosis (MAP) that has been considered to serve as a model for schizophrenia, I present the findings that there is a reduction in the dopamine transporter density in the basal ganglia and the frontal cortex in patients with MAP and the reduction is related to the prolonged psychiatric symptoms. In the half of my talk, I focus on the measurements of domapine D2 receptor and serotoin 5-HT2A receptor occupancy using PET after administration of atypical antipsychotic agents. Characteristics of these two receptors are deemed to represent pharmacodynamics of treatment effect and side effects (notably extrapyramidal signs). Recently, current reliance on plasma kinetics as the main basis for dosing regimens of antipsychotics has been questioned (Tauscher et al, 2002). It is also probable that any relation between plasma kinetics and bran kinetics of drugs may vary with different ethnic groups. PET with [11C]raclopride and [11C]N-methylspiperone allows us to directly quantify these two receptor occupancies, respectively in individuals who are given an agent. I believe that data obtained from PET will provide a means of opting for optimum dosing regimens.

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SESSION2

The Search for Alternatives to Randomised Comparative Studies

Peter Boyle Division of Epidemiology and Biostatistics, European Institute of Oncology, Itary Governments and Non-Governmental Organisations are increasingly mandating and urging a larger participation in Clinical Trials. At the same time, there are an increasing number of hurdles to conducting such trials, an increasing burden in administering clinical trials, an increasing formal move against having placebo control arms in any trials and an increasing reluctance on the parts of (lay) Ethics Committees and indeed patients to accept the whole concept of randomisation. All this taking place at a time when there are such major advances in how we look at disease, and how we can look at disease. The threat to placebo controlled trials, the most visible being from the revision of the Declaration of Helsinki, is a major handicap in many fields of Medicine where there is no established and agreed standard of care. In addition, there has always been a major puzzle about why some patients respond to particular therapy while in almost identical circumstances, others do not. With increasing insights into molecular genetics parts of this puzzle are about to become clear. For example, Herceptin® (Trastuzumab) is used to treat HER2-driven metastatic breast cancer with some outstanding responses. Gleevec® (imatinib mesylate) is indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) chronic myeloid leukemia (CML) in blast crisis, accelerated phase, or in chronic phase after failure of interferon-alpha therapy. These are pioneering breakthroughs and will soon be followed by more in a similar vein. Even common drugs used in common diseases can have great variation in their outcomes in individual patients and genetic explanations of such differences are starting to be sought. It is possible, starting in a disease such as cancer where standards of care have been established for many diseases, that in coming years the randomised trial will be outdated and replaced (perhaps) by the creation of a large clinical and biological database with diagnostic, treatment, genetic and response information available which will allow the basis of the necessary comparison. What was futuristic only a few years ago is becoming increasingly the reality.

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SESSION4

Genetics as a means of understanding intrinsic ethnic differences -Genetic variation on metabolic/transporter/receptor-

Junichi Azuma Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, JAPAN Many individuals of Asian descent are extremely sensitive to even small doses of alcohol, principally because of the different activity of key enzymes in alcohol metabolism. Those that seem to predispose individuals to unpleasant effects after alcohol consumption are common in certain ethnic groups including Asians. This phenomenon is not limited to the alcoholic beverages. It is well known that different people frequently show varied responses to drugs. Even if a drug of the same amount is taken, an individual difference occurs in the effectiveness and degree of a side effect. Then unpredictable reactions that can result in significantly high morbidity and mortality may happen. An effective rate of most drugs is roughly 60-70%, and "a non responder" exists inevitably. One of a cause of this individual difference includes a hereditary factor. It is important to realize that human genetic variability can affect one or more of the stages in drug response: drug transporters, drug metabolizing enzymes and the intended and/or unintended drug target molecules. Individual differences in genes and their protein products can affect how well- or poorly- an individual responds to a particular drug treatment. We already know quite a bit about the enzymes in the liver that play critical roles in drug metabolism. Many of these enzymes exist in different forms within the human population. Many examples of exaggerated responses to drugs attributable to inherited traits have been observed after a "normal" dosage. Certain adverse drug reactions could be caused by genetically determined variations in the activity of drug-metabolizing enzymes. The polymorphism is a difference in DNA sequence found at 1% or higher in a population. Polymorphic expression of some drug metabolizing enzymes divides the human population into 2 groups: "poor" metabolizers, who express dysfunctional or inactive enzymes, and "extensive" metabolizers, who express enzymes having normal activity. Thus, some people have very active drug metabolism while that of others is much more sluggish. Perhaps the most important of the polymorphically expressed enzymes among oriental population are CYP2C19 and CYP2D6, and NAT2. The impact of NAT2 genetic polymorphisms for the development of ionized+rifampicin-induced hepatotoxicity will be discussed. The metabolic activity of CYP2D6 and its genetic polymorphism between Orientals and Caucasians are given to emphasize the importance of intermediate metabolizers in Asia.

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The information on the role of polymorphic drug transporters and drug receptors for effectiveness of drug therapy is scarcer, although some promising examples are reported in drug treatment although some promising examples are reported in drug treatment in spite of some controversial reports. An overview about our present knowledge how polymorphic genes can influence the drug efficacy and toxicity will be presented.

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SESSION5

New Monoclonal Antibody Approved for Advanced Breast Cancer: Trastuzumab

Shin-ichi Nihira Chugai Pharmaceutical Co., Ltd., Japan The accumulation of a large amount of human genome information recently brings up a new paradigm in the cancer chemotherapy, in which “tailor-made” cancer chemotherapy might be applied based on patients’ genetic background. HER2 is a member of human epidermal growth factor receptor family, possessing protein kinase activity in its cytoplasmic domain of the molecule. There were many evidences from preclinical and epidemiological studies that indicated; (1) amplification of HER2/neu gene and subsequent HER2 protein overexpression in tumor cells was observed in 25-30% of human breast cancer patients, (2) HER2 molecules overexpressed on tumor cells contributed to increasing cell proliferation, tumourigenicity and metastatic potential, (3) amplification of HER2/neu correlated with poor prognosis of the disease, including shorter disease-free survival and overall survival. These evidences suggested that HER2 overexpression caused by HER2 gene amplification on tumor cancer was a promising candidate for a novel molecular target of breast cancer therapy utilizing the humanized monoclonal antibody. Trastuzumab was a recombinant humanized monoclonal antibody generated by Genentech for the treatment of HER2 overexpressing/HER2 gene amplified metastatic breast cancer. Preclinical and clinical studies of trastuzumab demonstrated that the antibody has apparently anti-tumor activity for HER2 overexpressing/HER2 gene amplified metastatic breast cancer. Trastuzumab is the first anticancer drug, which should be prescribed for metastatic breast cancer (MBC) patients based on their status of HER2/neu gene amplification and subsequent HER2 protein overexpression. The development and standardization of Immmunohistchemistry (IHC) test and FISH test were a key strategy for clinical development of trastuzumab for MBC, since the up-front selection of patients with HER2 overexpression/gene amplification appropriately was the essential point of the success in the clinical studies of trastuzumab. In this presentation, I would like to briefly summarize the clinical results of Trastuzumab from the point of view of the drug development based on genetic analysis. HER2 diagnosis and the algorithm implemented in clinical practice for metastatic breast cancer treatment will also be discussed.

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SESSION5

The Human Approach to Target Validation and Drug Discovery

Alastair J. Riddell Pharmagene plc, UK Pharmagene is a drug discovery company focussed on the pre-clinical use of human tissue to improve the chances of success of drug candidates in the clinic. The company was founded in 1996, listed on the London Stock Exchange in 2000 and is based near Cambridge in the UK. It has a sales office in California and an agent in Japan. By commercialising its capabilities, Phase ZERO, which tests compounds in the human tissue environment and TargetEvaluator, a database of gene expression profiles in normal and diseased tissue, it has built a customer base in all three major markets. There has been strong growth in Japan. The talk will describe how the integration of gene expression analysis, protein localisation, cell-based assays and functional pharmacology can produce novel uses for existing molecules (“Indication Switch”) and help develop entirely novel drugs. Examples of how this integrated approach in the human context has led to three new lead drug discovery programmes will be described. The first is a peptide for the treatment of cystic fibrosis (PGN 0052), which will enter the clinic at the end of 2002. The second will show how two lead series have been optimised for irritable bowel syndrome (IBS). The third will illustrate the same for a novel treatment for migraine. All of these treatments act via novel mechanisms of action. This integrated approach is now available to customers as a Custom Validation Programme. Pharmagene intends to out-license the therapeutic programmes described above; the IBS and migraine leads will be out-licensed over the next 12-18 months and early discussions are invited; PGN 0052 will be out-licensed after clinical proof of principle.

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SESSION5

From Genomics to Drugs: Gene Haplotypes and Drug Response

Kevin Rakin Genaissance Pharmaceuticals, USA Medical scientists and researchers are mining the enormous volume of genetic data being made available through public and private human genome-mapping initiatives. The sheer volume of genetic diversity being discovered in human genes strongly suggests that the clinical variation seen in patient response to medication is due, in part, to gene variation. A variety of approaches have been proposed to find genetic markers that can be used in a clinical setting. Recently, major government and academic genome researchers have agreed that haplotypes are a powerful tool, and the most precise measurement of gene diversity, that can reduce the complexity of genetic information to a practical form. A haplotype is defined as the organization of nucleotides present at all of the known polymorphic sites in a gene or region of genomic DNA. Genaissance Pharmaceuticals has pioneered the industrialization of haplotype discovery and has determined haplotypes (HAP™ markers) for more than 5,500 human genes. By discovering these inherited differences that exist in human genes and correlating these markers with drug response, Genaissance is defining patient populations that respond best to a medication or have superior safety profiles. Genaissance is currently applying its expertise in three therapeutic areas (central nervous system, cardiovascular and inflammation). Genaissance has initiated the largest-ever prospective pharmacogenomic clinical trials. STRENGTH (Statin Response Examined by Genetic HAP™ Markers) studies I & II are designed to determine clinical associations between genetic markers (HAP™ Markers), and efficacy and safety for cholesterol lowering statin. The initial analyses of these studies have shown that HAP™ Technology can identify strong and frequent drug-specific haplotype associations to clinical response. Genaissance has agreements with three of the top five pharmaceutical companies as well as one of the premier biopharmaceutical companies: AstraZeneca, Biogen, Johnson & Johnson, and Pfizer.

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SESSION5

Toxicogenomics in USA --- Molecular Toxicological Approach in Drug Discovery and Development ---

Ikuo Horii Pfizer Global Research and Development, Nagoya Laboratories, Drug Safety Evaluation. Pfizer Pharmaceuticals Inc., Japan The genetic information as human genome has widely published with the potential to revolutionize the drug discovery process. Concepts of genomics have already been introduced for molecular targeting in drug discovery as a pharmacogenomics. In parallel with this approach, toxicologically responsible gene expression and the toxicity-related protein synthesis have been well recognized as toxicogenomics and toxicoproteomics. Recently the new concept of metabolomics has been additionally put in these toxico “-omics” as toxicopanimics in the field of molecular toxicology. Now discipline of toxicology is facing to a transitional phase. After the molecular targeting, a lot of new compounds are generated using the techniques of combinational chemistry that fit the target. Toxicologists are now obliged to screen these new compounds in great numbers and small amounts; that is, high throughput toxicology. To meet these needs, the feasibility of toxicopanomics (toxicogenomics / toxicoproteomics / metabolomics) in evaluating the toxicity of a new compound is attracting attention. Basically the approach from toxicopanomics is considered to be useful in the elucidation of toxicological mechanisms and therefore expected to be of valuable biomarker dealing with the adverse effects observed in post-marketing analysis. Since the manifestation of a toxic event is caused by the expectation of various genes, it can be referred to: (1) specifying the genes affected will read to the early detection or warning of subsequent adverse effects, and (2) automation / simplification of the analysis of gene expression and protein synthesis will enable comprehensive investigation that elucidates toxicological mechanisms on a molecular basis. The genes related to toxic events can be grouped, for example, as stress response, cell proliferation, apoptosis, DNA damage, inflammation, oxidative stress, drug metabolism, transporter, and so on. Recently, these genes are being identified for mouse, rat, dog, monkey and human, and being used as a tool in gene chip technology. Toxicoproteomics approach has been also recognized as practical evidence, which leads to exact toxicities. In addition, metabolomics-theory has been spotlighted as a new biomarker derived from toxicological responses as a metabolome, following the genome, transcriptome and proteome. These new molecular toxicological approaches would open the door for real toxicological safety assessment. In this occasion, the brief outcome on the 2002 workshop on pharmacogenetics / pharmacogenomics in drug development and regulatory decision-making, sponsored jointly by the FDA, DruSafe PhRMA and PWG, is to be introduced as a recent trend of regulatory implications.

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SESSION5

Regenerative Medicine

Yoshiki Sasai Institute for Frontier Medical Sciences, Kyoto University, Japan I discuss recent progress in regenerative medicine focusing on ES cell technology. We recently identified a stromal cell-derived inducing activity (SDIA), which induces differentiation of neural cells, including midbrain TH+ dopaminergic neurons, from mouse embryonic stem (ES) cells. Furthermore, it has been confirmed that SDIA induces efficient neural differentiation also in primate ES cells. Another type of CNS neurons that can be induced at a high efficiency is the motor neuron lineage. We discuss the differentiation potency of ES cells in this SDIA system. In addition, 8% of the colonies contain large patches of pigment epithelium of the retina. The SDIA method provides an unlimited source of primate cells for the study of pathogenesis, drug development and transplantation in degenerative diseases such as Parkinson’s disease and retinitis pigmentosa. I would also like to introduce some government-based development program of medical industry development in Kobe.

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SESSION6

Lessons Learned from a Global Clinical Trial: an Experience of 'RENAAL' Study

Kiyoshi Kurokawa Institute of Medical Sciences, Tokai University, Japan. Development of innovative new drug entities are key to improve healthcare and and quality of life of the people of the world. Even in the era of genetic and genomics, effective clinical trials is an essential and critical component of drug development. Further, the quality of clinical trials depends upon many factors, but the backgrounds of patients enrolled. This factor has become more important in this new century since such a new innovative entity should become available to wider patients across the national boundaries. Nonetheless, there must be considerations for ethnic and other backgrounds of the patients populations studies. We have conducted an international clinical studies examining the effects of angiotensin II type 1 receptor antagonist, Losartan, on the progression of nephripathy in type 2 diabetic patients called RENAAL, which began 1996 and ended early 2001. The study enrolled more than 1,500 patients in 28 countries. Some of the initial data were published in September 20 issue of NEJM. One of characteristics of RENAAL was 17% of the patients were Asians, with 96 from Japan and 92 from Hong Kong. The analyses of data showed the significant effects of Losartan, but the subpopulation analyses provided several interesting hypotheses. In this presentation, I shall present some data with pertinent hypotheses generated through this study.

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SESSION6

Revolution in Asian Drug Development? A Korea – Japan Experience

Henk J. de Koning Gans Pharmacia K.K., Japan Although ICH E5 has changed global drug development, there are still many hurdles either real or perceived. Pharmacia Inc. started the development of tolterodine, a new anti-muscarinic for the treatment of the treatment of Overactive Bladder (OAB) before the implementation of ICH E5. The development was designed in the traditional way: Key studies in Western countries, primary submission in Europe and US, followed by submissions in the rest of the world with or without some small local studies and, for Japan, a separate program. After the successful introduction of tolterodine in Europe/US, the Company developed and introduced an extended release (ER) tolterodine formulation in Europe/US. The Company considered the ER formulation a better formulation because of improved tolerance and a slightly better efficacy. Pharmacia decided to develop the ER formulation for Japan. At that time, the need for data other than from Western studies was becoming more apparent in the whole Asian region. In order to meet the Japanese requirements and the need for adequate data in an Asian population, Pharmacia decided to perform a Phase III study in Korea and Japan. The study design was identical to the study used for the registration in Europe/US. This proposal was discussed with and accepted by the Korean and Japanese health authorities. It was a 12 week, randomized, double blind study with both an active (oxybutynin) and placebo control arm. The primary endpoint was median % change from baseline in reduction of urinary urge incontinence (UUI) episodes. The study showed similar results as previously seen in the Europe/US study. The enrolment period was from January to June 2001 (600 pts). The special steps, taken to make this unprecedented enrolment possible, will be presented in detail. This study clearly demonstrates that high quality studies can be performed in a timely fashion in Japan and the Asian region at large.