Program Tuesday, October 28, 2003 QT Symposium (Satellite Meeting) A meeting satellite to the 4th Kitasato University - Harvard School of Public Health Symposium to discuss latest drug developments in the understanding QT prolongation 9:00 - 9:10 Opening Remarks

Masahiro Takeuchi (Kitasato University, The Kitasato Institute) Topic 1 Non Clinical Pharmacology and Clinical Assessment of QT Prolongation

Chairperson: Kihito Takahashi (Banyu Co., Ltd.) 9:10 - 9:40 Non Clinical Pharmacology

- To Cover Testing Paradigms and Latest ICH Thinking (ICH S7B) - Robert Wallis (Pfizer)

9:40 - 10:10 Clinical Assessment of QT Prolongation Kazuhiro Sase (National Cardiovascular Center)

Topic 2 The Link Between Non Clinical and Clinical Testing

Chairperson: Kazuhiro Sase (National Cardiovascular Center)

The Link between Non Clinical and Clinical Testing - Are Non Clinical Tests Predictive of Clinical Effects? -

10:10 - 10:35 Mike C. Perkins (Pfizer) 10:35 - 11:00 Alan S. Bass (Schering-Plough Research Institute) 11:00 - 11:15 Break Wrap Up and Conclusion

Chairperson: Mike C. Perkins (Pfizer) 11:15 - 12:00 Above Speakers plus Keiji Yamamoto (Takeda Chemical Industries, Ltd.)

1

Main Symposium 13:00 - 13:10 Opening Remarks and Welcoming Address

Tadayoshi Shiba (Kitasato University) 13:10 - 13:20 Congratulatory Remarks

Shuichi Kishida (Ministry of Health, Labour and Welfare) Session 1 Global Program: Is There a Reality?

Chairperson: Declan P. Doogan (Pfizer) with his Welcoming Address 13:25 - 13:45 Lessons Learned from Three Global (Mega-) Clinical Trials

Masahiro Takeuchi (Kitasato University, The Kitasato Institute) 13:45 - 14:05 Clinical Perspective; Template on Global Clinical Study Protocols

Masaaki Kuwahara (J-PMA, Takeda Chemical Industries, Ltd.) 14:05 - 14:25 Statistical Consideration

Hiroyuki Uesaka (J-PMA, Eli Lilly Japan K.K.) 14:25 - 14:45 Cost-Trends

Comparison of the Cost: Japan vs. Rest of the World Including Asia Katsuyoshi Shimatani (Pfizer)

14:45 - 15:35 Panel Discussion

Above Speakers plus In-Jin Jang (Seoul National University, Korea), Chin-Fu Hsiao (National Health Research Institute, Taiwan), Kosuke Kozaiwa (Nippon Boehringer-Ingelheim Co., Ltd.) and Toshihiko Morikawa (Takeda Chemical Industries, Ltd.)

15:35 - 15:50 Break Session 2 Regulatory Updates and Clinical Trends

Chairperson: Yasuhiro Fujiwara (National Cancer Center Hospital) and Masahiro Takeuchi (Kitasato University, The Kitasato Institute)

15:50 - 16:10 Review of Bridging Programs, Regulatory Successes

2

Koji Todaka (Pharmaceuticals and Medical Devices Evaluation Center) 16:10 - 16:30 A Case Study in the Value of Harmonisation

Yoshikazu Hayashi (Ministry of Health, Labour and Welfare) 16:30 - 17:10 Panel Discussion

Above Speakers plus Yi-Jin Chiou (Center for Drug Evaluation, Taiwan) and Yoshiki Kaneiwa (Eli Lilly Japan K.K.)

17:10 - 17:30 Large Scale Clinical Trial Network

Mitsue Hirota (Ministry of Health, Labour and Welfare) 17:30 - 17:50 Industry Performance Metrics

How Does Japan Compare with the West? Are things improving? Stuart R. Walker (CMR International Ltd.)

17:50 - 18:10 The Internet as a Means of Recruitment, Patient Education, Data Management and

Monitoring Stephen E. Wilson (U.S. Food and Drug Administration)

18:10 - 18:50 Panel Discussion

Above Speakers plus Masaru Iwasaki (Aventis Pharma Ltd.), Masayoshi Kawaguchi (Eisai Co., Ltd.) and Gwyn Thomas (Wyeth Lederle Japan, Ltd.)

18:50 - 20:50 Reception

3

Wednesday, October 29, 2003 Session 3 Practical Use of ICH Guidelines for Bridging / Global Clinical Trials

(TV-Conference) Chairperson: Stephen W. Lagakos (Harvard School of Public Health)

8:30 - 9:10 ICH E5 Q&A

Robert T. O'Neill (U.S. Food and Drug Administration, via TV) Surrogate Markers Susan S. Ellenberg (U.S. Food and Drug Administration, via TV)

9:10 - 9:30 How Should We Plan and Conduct Asian Studies?

- From the Reviewer's Viewpoint - Kazuhiko Mori (Pharmaceuticals and Medical Devices Evaluation Center)

9:30 - 10:00 Panel Discussion Above Speakers plus Masuhiro Kato (AstraZeneca K.K.) and Satoshi Miki (Chugai Pharmaceutical Co., Ltd.) (Close TV-Conference)

10:00 - 10:15 Break Session 4 OMICS: Genomics, Proteomics and Metabolomics

- How Can They be Used to Enhance Product Approval? - Chairperson: Kenichi Arai (Institute of Medical Science, University of Tokyo)

10:15 - 10:45 How OMICS has Influenced Paradigms?

- How Can They be Used to Enhance Product Approval? - Aidan C. Power (Pfizer)

10:45 - 11:15 Japan Perspective on PGt/PGx in the Drug Development and Approval Process

Junichi Azuma (Osaka University) 11:15 - 11:35 Japan Issues and Counter Measure for Real Implementation of Genome Based

Clinical Trials Sanae Yasuda (J-PMA, Eisai Co., Ltd.)

4

11:35 - 12:15 Panel Discussion Above Speakers plus Jin-Ding Huang (Department of Health, Taiwan) , Osamu Sato (Daiichi Pharmaceutical Co., Ltd.) and Eric W. Lewis (GlaxoSmithKline K.K.)

12:15 - 13:40 Lunch Session 5 Other Novel Technology Update: Modeling Technique, Biomarkers,

Disease Surrogates, Data Mining Chairperson: Hiroo Imura (Council for Science and Technology Policy, Cabinet Office)

13:40 - 14:00 Modeling Technique: Structural Genomics / Structural Proteomics

Haruki Nakamura (Osaka University) 14:00 - 14:30 Biomarkers and Medical Imaging in Clinical Trial (PET, MRI, etc.)

Wayne O. Carter (Pfizer) 14:30 - 14:50 Application of PK/PD Modeling in Drug Development

Amarnath Sharma (Pfizer) 14:50 - 15:10 Bridging Strategies Using Clinical Trial Simulations

Russell Wada (Pharsight Corporation) 15:10 - 15:50 Panel Discussion

Above Speakers plus Kazuhiko Yanai (Tohoku University) 15:50 - 16:10 Break 16:10 - 16:30 Summary and Conclusion

Stephen W. Lagakos (Harvard School of Public Health) 16:30 - 16:40 Closing Remark

Masahiro Takeuchi (Kitasato University, The Kitasato Institute)

5

QT SYMPOSIUM

Non-Clinical Pharmacology

Robert. M. Wallis Pfizer Global Research and Development, Sandwich, UK

Prolongation of the QT interval of the ECG is recognised to be an important issue for Drug Discovery and Development and for Regulatory Authorities. A diverse range of drugs, including histamine H1 antagonist, gastric prokinetic agents and antibiotics have been withdrawn from the market because of their association with a life threatening arrhythmia, Torsade de Pointes (TdP), for which QT prolongation is used as a biomarker. More than 50 drugs have been associated with a risk, or possible, risk of TdP (www.torsades.org) and greater than 90% of these agents have been shown to block the cardiac rapidly-activating delayed rectifier potassium current, IKr. A hierarchy of testing strategies can be developed to minimise the risk of QT prolongation in new chemical entities. High throughput radioligand binding and fluorescence based functional assays can be used to screen many compounds to determine the structure activity relationship for the cardiac ion channel of interest. Confirmation of activity at selected cardiac ion channels can be demonstrated using patch clamp assays. It is, however, important to recognise that compounds can block multiple cardiac ion channels and that effects on the ECG morphology cannot be wholly predicted from in vitro assays. An evaluation of compound effects in vivo is therefore essential to define the pharmacological liability of new chemical entities to delayed cardiac repolarisation in man. For example, the selective IKr blocker, sotalol, inhibits IKr, prolongs the action potential duration recorded from canine Purkinje fibres and prolongs the QT interval in the dog, monkey and man and is associated with TdP. In contrast, the mixed ion channel blocker, verapamil inhibits IKr and calcium channels, and therefore shortens the action potential duration recorded from canine Purkinje fibres and generally shortens the QT interval in vivo and is not associated with TdP in man. Thus, although both compounds are IKr blockers they exhibit different in vivo profiles. It is recognised that a wide range of chemical entities can inhibit the IKr current at some concentration, including those not associated with TdP. Therefore, an observation of whether a compound can inhibit the IKr current may be of limited value in predicting the potential of new chemical entities to prolong QT in man. It has been suggested that understanding the relationship between the potency of drugs to inhibit IKr and the predicted or actual plasma concentrations in man may be a better predictor of the potential of drugs to prolong the QT interval in man (Redfern et al (2003) Cardiovascular Research 58 32-45). Overall, non-clinical assays are available to determine the pharmacological liability of a new chemical entity to delay cardiac repolarisation in man. However, no one assay is fully predictive of effects in man and an integrated approach, including relating effects to human plasma exposures, is required.

6

QT SYMPOSIUM

Clinical Assessment of QT Prolongation

- From Bedside to Bench, Bench to Bedside -

Kazuhiro Sase National Cardiovascular Center, Osaka, Japan

Clinical Importance of QT Prolongation The QT interval (measured from the beginning of the QRS complex to the end of the

T wave) of the electrocardiogram (ECG) represents the total duration of ventricular activation and recovery.

When the QT is prolonged, there is an increased risk of life-threatening tachyarrhythmia such as torsade de pointes (TdP), especially when combined with risk factors like electrolyte abnormalities, bradycardia, and malnutrition.

While the patient with self-terminating TdP may experience syncope, the one whose torsade degenerates to ventricular fibrillation suffers sudden death.

Lessons Learned from Congenital LQTS Long QT syndrome (LQTS) can be divided into congenital (idiopathic) and acquired

(e.g. pharmaceutical-induced) forms. Currently, mutations have been identified in 7 LQT genes (LQT1-LQT7), including sodium channels (LQT3 and LQT4) and potassium channels. Although patients with the LQT3 mutation tend to have fewer cardiac events, they tend to be more lethal ones. Risk stratification with genotype, corrected QT interval (QTc), and other modifiers is proposed.

TdP resulting from congenital LQTS is treated with beta blockade, surgical sympathetic interruption, pacing, and implantable defibrillators. Gene-specific therapy is under investigation, including the use of sodium channel blockers in LQT3 and potassium administration in LQT1 patients.

Risk Stratification and Treatment of Acquired LQTS Lessons learned from the rare but important congenital LQTS now applies to more

common situations. Acquired LQTS by pharmacological blocking of ion channels is not limited to class Ia and class III anti-arrhythmic drugs. A number of non-antiarrhythmic drugs have reported to have adverse-effect of delayed cardiac repolarization and fatal/non-fatal TdP, resulting in withdrawal from the market or denial of marketing

7

authorization. Treatment of the acquired LQTS requires identification and correction of the cause of

LQTS (e.g. discontinue proarrhythmic drugs). Although recent studies suggest risk-stratification might be possible for acquired LQTS before exposing risk factors to patients, clinicians should consider the risk management of QT-prolonging as well as interacting medications.

Clinical and Pre-Clinical Assessment in the Post-Genome Era

Assessment of QT prolongation would continue to be used as an important surrogate from the clinical as well as regulatory perspective as appreciated in ICH-S7B draft guideline. However, as more molecular and cellular details of "Ion Channelopathies" (e.g. Brugada syndrome) being characterized, we are learning that the QT prolongation is one of the many surrogates for fatal arryhthmia and sudden cardiac death.

With the catalog of all human genes and millions of genetic and/or molecular markers finally in hand, we've just had a critical resource with which to begin the task.

8

QT SYMPOSIUM

The Link between Non-Clinical and Clinical Testing

Are Non-Clinical Tests Predictive of Clinical Effects?

Mike C. Perkins Pfizer Global Research and Development, Sandwich, UK

Several drugs have been withdrawn from the market because of their association with the arrhythmia, Torsades de Pointes (TdP), for which QT prolongation is used as a biomarker. Most of these agents have been shown to block the cardiac rapidly activating delayed rectifier potassium current, IKr. This presentation will review whether the non-clinical pharmacology of these and other agents might have predictive value in the determination of clinical effects. I will review this hypothesis based on: • Standard agents with known effects on QT and arrhythmia with the principal target

being HERG/IKr. • The study safety margins of these compounds and will pose the question whether all

HERG blockers are the same by evaluating repolarisation assays and in vivo evaluations, including proarrhythmia, pharmacokinetics and drug-drug interactions

The conclusion that an integrated risk assessment provides clear pointers to the likely possible effects in man will be examined.

9

SESSION 1

Lessons Learned from Three Global Clinical Trials

Masahiro Takeuchi Division of Biostatistics, Kitasato University, The Kitasato Institute, Japan

The new international drug development by regulatory bodies, “The International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use”, known as ICH, was started in 1990 to unify the necessary documentation and its formats of new drug application among three regions, the US, the EU, and Japan. A new guideline established in 1998, known as the ‘E5 guideline’ allowed the extrapolation of already existing foreign clinical data to new regions. The E5 guideline makes it possible for sponsors to utilize the foreign clinical data as a part of the NDA submission to regulatory agencies, and also to avoid unnecessary clinical trials only by repeating similar types of clinical trials. This movement provides patients with new and innovative drugs in a timely fashion. The application of the E5 guideline requires a special trial, known as a ‘bridging study’, used for the extrapolation of the existing foreign data. The main purpose of the bridging study is to show a similar profile of a tested drug in new regions to the one derived from the foreign data. The sponsors are required to examine the profile in terms of two aspects, intrinsic and extrinsic factors and to show no variability of the profile and no different operation of clinical trials among regions. The concept of the bridging strategy simultaneously, makes global drug development possible. The bridging strategy is just a ‘one-way process’ and we can extend the idea to the ‘two-way process’. The global drug development can adopt the ‘both way process’ simultaneously and show no difference in the two factors among regions. We will examine the indication of the two conditions, intrinsic and extrinsic factors, and investigate possible strategies implemented in a global study. Three global clinical trials will be taken as examples, then review the aspects of the trials regarding a study design, the definition of the targeted population, a statistical analysis, surrogate markers, etc. and investigate the strategies taken to cope with the two conditions. Lastly we will discuss the future issues concerned.

10

SESSION 1

Points to Consider of Protocol on Multinational Trial

Masaaki Kuwahara Takeda Chemical Industries, Ltd., Japan The concept of bridging study were proposed as new challenges to drug development. After implementation of the ICH E5 guidance, several drugs have been approved in Japan. An obvious benefit of this concept includes the extrapolation of the foreign clinical data. Next step, we might consider that global clinical studies aimed at simultaneous worldwide approval of new drugs. This is a much more challenging scenario, and there are some key factor for successful multinational trial. To focus on a issue for protocol, I would like to briefly summarize the points to consider of protocol on multinational trial and the flexibility of protocol.

11

SESSION 1

Statistical Considerations for Multi-Regional Trials

Hiroyuki Uesaka Lilly Research Laboratories Japan, Eli Lilly Japan Since 1998 when the ICH-E5 guideline became effective in Japan, new medicinal products have been developed using this guideline. However, in order to introduce a new drug as early as possible not only in U.S. and EU clinical practice, but also in Japan and other Asian countries, simultaneous development of a new medicinal product among these regions is thought to be the most efficient way. A multi-regional trial is one possibility in this situation. However, there has only been little discussion among regulators, academia and industry about design of a multi-regional trial and statistical analysis of data. Discussion of ways to show efficacy and safety in the Japanese population has also been limited The multi-regional clinical trial would be a dose-response trial for bridging, a confirmatory trial for a relatively common disease, or a confirmatory trial for a rare disease or fatal disease with true endpoint. The following aspects are discussed from a statistical point of view focusing on a confirmatory trial: analysis of ethnic factors, important design features, statistical analysis of efficacy and sample size.

12

SESSION 1

Cost-Trends

Comparison of the Cost: Japan vs. Rest of the World including Asia

Katsuyoshi Shimatani Pfizer Japan Inc., Tokyo, Japan The cost of developing new medicines has been increasing both globally and within Japan. For the purpose of understanding the impact on the business, we did a comparison of phase II/III development costs between Japan, the USA and Europe. The comparison was made on four protocols in three therapeutic areas: metabolic disease, infectious disease and genitourinary disorders. The protocols selected for comparison were chosen because of similar designs between the different regions, allowing for direct comparison of equivalent cost categories. The metabolic study is a global study and the urinary disorder study was a bridging study; despite very closely matched protocol designs between Japan and the West, the two infectious disease studies conducted in Japan were stand-alone development strategies. All studies were conducted under either International Conference on Harmonization guidelines for Good Clinical Practice or Japan’s New Good Clinical Practices. The studies were conducted (first patient visit to last patient visit) between 1999 and 2003. The comparison segmented the total protocol costs into the following categories: total CRO (clinical and biometrics), central laboratory, advertising, clinical and other. Clinical costs were further broken down into the following categories: direct, indirect and SMO. We found that the cost of developing a new chemical entity is two to four times higher in Japan than other ICH regions and other Asian countries.

13

SESSION 2

Bridging Studies: Any Need for Science?

Koji Todaka Pharmaceuticals and Medical Devices Evaluation Center, Japan

As of September 1, 2003, eighteen new drug applications using prospective bridging strategy have been approved by Japanese regulatory authority, Pharmaceuticals and Medical Devices Evaluation Center (PMDEC). They are fexofenadine, oseltamivir, anastrozole, sumatriptan, zolmitriptan, palivizumab, oseltamivir dry-syrup, risedronate, eletriptan, omeprazole- clarithromycin-amoxicilline combination, exemestane, brinzolamide, sumatriptan nasal spray, leflunomide, infliximab, imatinib and tegafur-uracil-folinate combination. Another drug is not mentioned here because neither PMDEC’s review nor product labeling is open to public yet. Generally speaking, the bridging strategy seems to have a high winning percentage. This is partly due to the fact that a typical bridging extrapolates large placebo-controlled randomized studies in Western countries to Japanese population. Additionally, most of those drugs have already been available and described well in every day practice overseas, which includes information regarding rare adverse drug reactions. The Japanese regulatory authority is to get such plentiful data with quality to make a good decision provided that results of bridging studies are analogous. There is a catch called ethnic factors, both intrinsic and extrinsic. Not in a few cases, especially extrinsic factors such as differences in medical practice or a change due to chronological gap in studies were the serious points of contention. These arguments were sometimes not very fruitful because both parties, the PMDEC and a sponsor, have no decisive data. Accordingly, I think judgments regarding bridging success or failure deserve scientific verification. For example, whether post-market efficacy and safety of the bridged drug in Japanese population resemble those in Western countries could be assayed if data were collected to this end. This kind of information will be important to tune both future bridging studies and review process.

14

SESSION 2

A Case Study in the Value of Harmonisation

Yoshikazu Hayashi Ministry of Health, Labour and Walfare, Japan The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a tripartite initiative among regulatory agencies and the research-based pharmaceutical industry in the EU, the US and Japan. ICH has developed more than 50 guidelines, which have achieved a remarkable results in promoting international harmonisation of technical requirements for the registration of new drugs, and thus in promoting public health in ICH regions. Among other ICH guidelines, ICH GCP (E6) and Ethnic Factors (E5) have had a profound impact on the global utilization of clinical data as well as the medical practices in Japan. Many non-ICH countries in Asia have quickly taken the spirit of ICH guidelines, based on their own need, into their regulatory practices. But sometimes the introduction of some ICH guidelines may have brought non-ICH countries to difficulty due to their heterogeneous regulatory capability and available resources. ICH GCG was formed in 1999 to interact between ICH and non-ICH countries. GCG is currently planning to hold the Satellite Session on “Partnership in Harmonisation” in ICH6 held in November 2003 envisioning to promote the interaction between ICH and non-ICH countries. Japan is, based on its own experience, aware of its large part to foster better interaction between ICH and non-ICH Asian countries through GCG, APEC and ASEAN towards the goal of improving access of innovative drugs to the patients in a timely manner.

15

SESSION 2

The Large Scale Clinical Trial Network

Mitsue Y. Hirota Ministry of Health, Labour and Welfare, Japan

The Ministry of Health, Labor and Welfare (MHLW) proposes an action plan to support innovation in the clinical trial (Chiken) environment. MHLW plans to support for establishment of the “Large Scale Clinical Trial Network” (hereinafter “the network”) for conducting clinical trails in Japan. The aim of establishment of the network is to ensure availability better medicines to Japanese patients.

Background The situation of conducting clinical trails in Japan faces serious problem. The problem is called “hollowing-out of clinical trials” This means that not only foreign manufactures but also domestic manufactures sift the sites where they conduct clinical trials from Japan to foreign countries. Clinical trial is the final and indispensable stage during the development of pharmaceuticals. Although, no manufactures can put his pharmaceuticals on the market without conducting clinical trials, the number of clinical trials conducted in Japan is getting smaller and smaller. For instance, the number of initial clinical trial notifications decreased from 160 cases in 1993 to 43 cases in 2001. Another example shows the number of repeat clinical trials notifications dropped from 1200 cases in 1993 to 424 cases in 2001.

Action Plan MHLW organizes a formation of a network comprising a number of medical institutions such as A) the National Centers and institutions for advanced and specialized medical care, B) Designated function hospitals and C) hospitals designated for clinical training. Over the next three years, MHLW intends to establish such network for 10 therapeutic categories such as cardiovascular and pediatrics. In the plan, MHLW also intends to establish a Secretariat as a center of these networks. In other words, MHLW plans to center these networks on the secretariat. Japan Medical Association (JMA) is going to be the secretariat.

MHLW intends to improve the Japanese clinical trail environment with the establishment of the network. MHLW plans that the network will enable to secure promptly the number of cases required for clinical trials. This function of the network will be able to provide high quality clinical trial data with speedy manner and low cost. MHLW has a view that the network will solve the problems that are pointed out as causes of hollowing-out of clinical trials. These causes are as follows; 1) Cost of conducting clinical trials is much expensive, 2) The quality of clinical trials is poorer than those conducted in foreign countries and 3) Conducting clinical trials is much time consuming in comparison with clinical trials conducted abroad.

16

SESSION 2

The Internet as a Means of Recruitment, Electronic Data Capture, Monitoring, Patient Education and Data Management – a Regulatory Perspective

Stephen E. Wilson Food and Drug Administration, USA With the expanding utility and popularity of the internet, researchers have developed a large number of important business applications relevant to the conduct of clinical trials -- including tools for patient recruitment, electronic data capture (EDC), monitoring, data management and patient education. A growing number of vendors and consultants offer services to help with the management of trial operations and procedures, and the collection and processing of clinical study data for submission to regulatory agencies. The FDA, with regulatory responsibility for the monitoring and conduct of clinical trials and for the review of information collected and described by sponsors applying for permission to market new medical products, is particularly interested in assuring the quality and confidentiality of these internet-based trial operations. In 1997 a new US regulation (21 CFR 11) went into effect that, for the first time, made it possible for sponsors to archive and submit the electronic information and data required by the Agency. This regulation, in describing “good practice” regarding the establishment and operation of computerized systems, is intended “to permit the widest possible use of electronic technology, compatible with FDA’s responsibility.” In designing and implementing internet-based systems for clinical trials sponsors and vendors need to carefully consider regulatory requirements intended to assure the security, privacy and quality of the information from clinical trials. This presentation will comment on US regulatory considerations in describing basic features of these systems and their potential application in the future.

17

SESSION 3

The ICH E5 Question and Answer Document: Status and Content

Robert T. O’Neill Food and Drug Administration, USA The E5 Implementation Working Group has been developing a Question and Answer document to help clarify aspects of interpretation of points covered in the E5 guidance and to clear up perceived misunderstandings of the intent of E5. The Question and Answer document deals with those areas of E5 for which it was felt that consensus could be reached on how E5 was being implemented in the subsequent years after its publication. The current status of the Question and Answer document will be discussed as well as the content of the ten questions and answers that now make up the document. Details of an answer to one of the questions will be provided, along with some comments regarding the statistical implications of these Q & A's for study planning, design and analysis.

18

SESSION 3

Bridging Studies in Vaccines Research

Susan S. Ellenberg Food and Drug Administration, USA The ICH E5 document, "Ethnic Factors in the Acceptability of Foreign Data," has generated substantial discussion. This document was developed in recognition of the lack of efficiency in duplicating large trials in multiple regions, but also of the potential for different populations to respond differently to pharmaceutical products. The document recommends that studies measuring parameters relating to the product's mechanism of action (e.g., pharmacokinetic/pharmacodynamic data) be considered to permit the clinical effects observed in one population to be extrapolated to a different population. Such studies are called "bridging studies." The application of bridging to therapeutic products can be complicated. It may not always be clear what measurements would be acceptable for bridging clinical findings to a new population, nor what level of similarity would have to be shown. Bridging studies in vaccine development, however, are performed routinely, using immune response(s) as the parameter of interest. Bridging studies are used to assess changes in formulation or manufacturing, in addition to extrapolation from one population to another. Experience in the vaccine area may provide useful insights into the process of bridging clinical data.

19

SESSION 3

How Should We Plan and Conduct Asian Study?

- From the Reviewer’s View Point -

Kazuhiko Mori Pharmaceuticals and Medical Devices Evaluation Center, Japan Asian Studies of clinical development for the new drug have developed over the last few years. From my personal experience, I asked several questions from pharmaceutical company about possibility of utilizing Asian studies for New Drug Application (NDA) in Japan. I also heard information from more than one expert that Asian countries rush to build the infrastructures for clinical development of new drugs, such as construction of adequately-resourced hospitals for clinical trials. The most probable causes of growing popularity for Asian studies are as follows. 1. Relatively low cost for studies in Asian countries compare to Japan 2. Highly motivated investigator and patient to join clinical trial result in drastic

progress on patient recruitment 3. Hope to escape from ethnic difference of efficacy/safety of pharmaceuticals among

countries in conducting multinational bridging study in Asian area 4. Decline of domestic clinical development from the begining of implementation of

ICH-GCP in Japan on 1997 In this kind of environment, we feel that it is high time to come up with practical solutions to utilize Asian studies for clinical development of new drugs. From the view point of reviewer, the first thing is “Seeing is believing”. It means concrete verification measure of GCP compatibility of trial. From 1997 to 2003, PMDEC have sent GCP inspection team to 3 Asian countries. The GCP inspection team visited 6 investigational site. We have found several difference between Japanese study and Asian study from these inspections. These findings are very beneficial to the progress of understanding the reality, good planning and conduct of well controlled clinical trial in Asian countries. Planning and conducting multinational bridging study in Asian area is attractive option for the grobal simultaneous development of new drug. On the other hand, it have unknown risk. For the time being, it is important to get a better grasp of situations on the ground of Asian study for both the pharmaceutical company and the drug regulatory authority.

20

SESSION 4

How OMICS has Influenced Paradigms?

- How Can They be Used to Enhance Product Approval? -

Aidan C. Power Pfizer Global Research and Development, Groton, USA This presentation will illustrate how pharmacogenomics is used at Pfizer to support research throughout the continuum from Discovery through Development. Understanding that all diseases are in part genetic is the beginning of the recognition that genetic information can contribute to solving critical problems that face the pharmaceutical industry - namely the rising cost of drug development and the attrition of candidates in the pipeline. Genetic information can help in the Disovery process through helping to prioritise useful approaches; it can be used to support decision-making in early development and it can be used to better understand drug response. Somatic genetic and genomic information are also being applied particularly in the area of oncology. Ultimately, pharmacogenomics may lead to the development of more precisely targeted medicines.

21

SESSION 4

Japan Perspective on PGt/PGx in the Drug Development and Approval Process

Junichi Azuma Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

An effective rate of most drugs is roughly 60-70%, and "a non responder" exists inevitably. Certain adverse drug reactions could be caused by genetically determined functional variations in drug targeting molecules as well as in drug-metabolizing enzymes and drug transporters. Thus, individual differences in genes and their protein products can affect how well- or poorly- an individual responds to a particular drug treatment. Both allele frequency and specific allele differences in polymorphic genes have been observed between different population ethnic groups. For example, the frequency of mutations in N-acetyltransferase is lower in Japanese than in Caucasian populations. Therefore, we might need to conduct pharmacogenomics (PGx) /pharmacogenetics (PGt) clinical studies during drug development at least once in Japan, though in silico trial could be another probability. Recognition of the impact of ethnical differences on PGx will lead comprehensive strategies for using the genome to drug development and finally to optimization of therapy for patients throughout the world. The perspective in the treatment of tuberculosis with isoniazid and rifampicin is one of the issues to be discussed as a case by use of PGx information. Possible difference in the treatment of heart failure with β-blockers among different ethnic groups is another subject of the talk. We can't reach the point in Japan without reference to the "Project on Realization of Medical Care System in Accordance with Individual Genetic Information". However, I will briefly talk about some other plans launched in Japan; The Japan Pharmacogenomic Consortium (JPGC), The PGx-Pharmacoeconomics (PEx) Working Group and the Pharmacogenetic TipTop Inc. (P-TipTop). The aim of JPGC is to build up the platform to conduct PGx/PGt clinical studies in Japan. Ten Japanese pharmaceutical companies have joined JPGC to investigate basic scientific and ethical issues such as informed consent, anonymity of handling of clinical samples and genetic data, validation of marker genes and SNPs, the role of central institutional review boards and so on. JPGC will verify these investigated issues by conducting a pilot clinical study. PGx-PEx Working Group is organized by the name of Tsutani Group, FY2003 MHLW funded project on "Rational use of pharmacogenomics in drug development and regulation”. The aim of the group is to clarify indispensable matters and an attention point that should facilitate the establishment of the guideline or the guidance in order to promote pharmaceutical development and the proper use of drugs using the PGt/PGx information. We have set up a joint venture P-TipTop so that genetic databases can be applied to optimize medication most suitable for each patient.

22

SESSION 4

Japan Issues and Counter Measure for Real Implementation of Genome Based Clinical Trials

Sanae Yasuda Eisai Co. Ltd., Tokyo, Japan

Nobody doubts that pharmacogenetics/pharmacogenomics (PG) will deliver a new generation of medicines. PG has a huge potential as an innovative technology for drug development. Nevertheless, PG application to clinical trials seems unrealistic at this moment in Japan, with the exception of a few researches on the effect of genetic polymorphism of drug metabolizing enzyme on pharmacokinetics.

Till now there have been few discussions on how to perform clinical trials with PG technology and how to incorporate these results into an NDA, even though there has been much attention paid to the importance of ‘personalized medicine’. On the other hand, there are perceived potential negative aspects of PG application to clinical trials, such as delays in trial progress due to difficulty in obtaining informed consent and increase of trial costs for genotyping. Therefore, we need to discuss these issues, and confirm the significance of PG on clinical development.

In 2001, the three ministries: Ministry of Health, Labor and Welfare; Ministry of Education, Culture, Sports, Science and Technology; and Ministry of Economy, Trade and Industry, jointly issued a guideline for ethical research of human genome and gene analysis. This guideline applies to PG researches other than clinical trials conducted in compliance with GCP. Meanwhile, the GCP guidelines do not specifically indicate how to treat ethical issues in relation to PG utilization. How do we conduct clinical trials ethically, respecting the patient’s rights and decisions? These should be clarified officially and publicly. It would also be important to make a guideline regarding how to collect and handle personal genomic samples and data with high security. The construction of such infrastructure is essential to perform PG trials, especially in Japan, where people are generally cautious about gene-related issues and clinical researchers are reluctant to initiate PG based trials without specific regulatory requirement/guidelines.

The ultimate issue with PG utilization in clinical development is how to quantitatively assess drug response. For identification of predictive genomic markers correlating with drug response, association has to be analyzed between genomic data and phenotype, which is clinical efficacy and/or side effect. Could we accurately discriminate between responder and non-responder? Gene analysis and its related technology will continue to show rapid progress. However, if clinical response is not adequately evaluated, we cannot possibly obtain valuable and reproducible results. I believe that PG application will succeed and lead to a real innovation in drug development when advanced technology and high-quality clinical trial are well combined.

23

SESSION 5

Protein Informatics: From Sequence to Structure and Function in Proteomics Research

Haruki Nakamura Laboratory of Protein Informatics, Research Center for Structural and Functional Proteomics, Institute for Protein Research, Osaka University, Japan (e-mail:harukin@protein.osaka-u.ac.jp;http://www.protein.osaka-u.ac.jp/rcsfp/pi/)

Information of the structures and functions of protein molecules and their mutual interactions that construct protein networks will rapidly increase as the consequence of the structural genomics and structural proteomics projects [1].

Our laboratory develops an advanced database for Protein Data Bank at Japan (PDBj), collaborating with Research Collaboratory for Structural Bioinformatics (RCSB) in USA, and Macromolecular Structure Database at the European Bioinformatics Institute (MSD-EBI) in England. We open the PDB browser and deposition site, and we collect, curate, and edit the deposited coordinates of proteins from Asian countries. Recently, we develop an XML (eXtensible Markup Language) description for the PDB data, collaborating with RCSB group (http://www.pdbj.org/PDB-ML/). The information of the biological and biochemical functions of proteins are now being collected and added to the original PDB-ML files.

In addition, we have developed several secondary databases. Among them, a database, eF-site (electrostatic-molecular surface of Functional site: http://www.pdbj.org/eF-site/), summarizes the protein molecular surfaces with their biochemical function information [2]. An algorithm using the clique detection method as an applied graph theory was developed for search of the eF-site database, so as to recognize and discriminate the characteristic molecular surfaces of the proteins. The method identifies the active site having the similar function to those of the known proteins, and could be used for the search of the complementary surface, in order to analyze the protein-ligand and the protein-protein interactions [3].

The static and dynamics features of protein structures are analyzed and predicted from their energy landscapes provided by the molecular simulations. For investigating the energy landscapes, we have developed our own algorithms of the multicanonical molecular dynamics and Tsallis dynamics [4-6], and applied them to predicting peptide structures, modeling loops, and flexible docking between a protein and the ligand [7-9].

References: [1] Kinoshita & Nakamura, Curr. Opin. Struct. Biol. 13, 396-400. [2] Kinoshita et al. (2001) J. Str. Funct. Genom. 2, 9-22 [3] Kinoshita & Nakamura (2003) Protein Science 12, 1589-1595. [4] Nakajima et al. (1997) J. Phys. Chem. B101, 817-824 [5] Fukuda & Nakamura (2002) Phys. Rev. E 65, 26105 [6] Kim et al (2003) Phys. Rev. E (2003) 67, 11105. [7] Nakajima et al.(2000) J. Mol. Biol. 296, 197-301 [8] Kamiya et al. (2002) Protein Science 11, 2297-2307. [9] Nakajima et al.(1997) Chem.Phys.Lett. 278, 297-301

24

SESSION 5

Biomarkers and Medical Imaging in Clinical Trial (PET, MRI, etc.)

Wayne O. Carter Pfizer Global Research and Development, Groton, USA The productivity of pharmaceutical companies measured by NDAs and R&D investments has been declining. To help solve this problem, Pfizer is investing in technologies to help accelerate safety and efficacy decisions in our clinical trials. Most clinical imaging methods are used for diagnostic or subjective assessment of the disease. Pfizer is developing methods to evolve these imaging and other technologies into quantitative endpoints. Several technology applications will be discussed including dynamic contrast-enhanced MRI and FDG-PET for oncology, cartilage volumetric measurements for osteoarthritis and PET and SPECT imaging for CNS applications.

25

SESSION 5

Application of PK/PD Modeling in Drug Development

Amarnath Sharma Pfizer Global Research and Development, Groton, USA The major objectives of the early clinical drug development are to select promising compounds and to identify safe and effective dose and dosing regimens for efficient drug development. These objectives can be achieved by quantifying the time course of pharmacologic response of the drug in relation to its plasma concentrations using PK/PD modeling. Reversible pharmacodynamic effects of drugs can be broadly classified as direct and indirect responses. For direct responses, a static function such as a linear model, an Emax model or sigmoid Emax model can often be applied to characterize PK/PD relationship. However, for some direct response drugs, effects are not apparently related to plasma concentrations because of equilibrium delay between the plasma compartment and site of action. In such cases, a hypothetical effect-compartment type approach can account for the equilibration delay. In contrast, for indirect pharmacodynamic responses, there is always a mechanistic delay for the development of a response even after the drug reaches the site of action. Thus, indirect response models should be used for describing the effects of drugs produced by indirect mechanism and the responses that exhibit mechanistic delay in their onset. The major requirements for PK/PD modeling are the availability of validated PD biomarkers for therapeutic effects and/or toxicity, understanding of pharmacologic behavior of the drug and pathophysiology of the disease and expertise in mathematical modeling. PK/PD characterization is also essential to evaluate complexity in PD responses such as tolerance and sensitization, to explain inter-patient variability in response and to identify biomarkers and validate them as surrogate endpoints. Two examples will be presented to demonstrate the application of PK/PD concepts to understand the complex time course of pharmacologic response of IL-12 and to validate a preclinical model for evaluation of anti-CD4 mAbs.

26

SESSION 5

Bridging Strategies Using Clinical Trial Simulations

Russell D. Wada, Kunihiro Sasahara, Yuying Gao Pharsight Corporation, USA The adoption of the International Conference on Harmonisation guidance (ICHE5) on the use of foreign clinical data has enabled data collected in clinical studies in the United States and Europe to be used in Japan for new drug approvals. The guidance discusses general criteria of acceptance, such as evidence of similar safety and efficacy in both regions. The guidance provides limited specific information regarding the criteria for similarity. Research in bridging study designs has focused on developing powerful and appropriate statistical methods to demonstrate similarity between Japanese and non-Japanese responses tested at a single dose. This presentation illustrates a method to design dose-response bridging studies considering data from all doses. The method is based on simulations of pharmacokinetic-pharmacodynamic and dose-response models. The method supports selection of doses, allocation of patients across dose groups, and inclusion criteria. We present a case study for the simultaneous design of dose-ranging trials in the West and in Japan for the development of a new HMG-coA reductase inhibitor in hypercholesteremia. Developing methods to bridge data from the West to Japan is the foundation for a dramatic gain in efficiency of global drug development.

Japanese

Caucasian

ED

50

LDL

Red

uctio

n (%

)

Dose

LDL Target

Japanese

Caucasian

ED

50

LDL

Red

uctio

n (%

)

Dose

LDL Target

Japanese

Caucasian

ED

50

LDL

Red

uctio

n (%

)

Dose

LDL Target

Japanese

Caucasian

ED

50

LDL

Red

uctio

n (%

)

Dose

LDL Target

Figure. Two definitions of similar efficacy illustrated with hypothetical mean LDL reduction vs. dose in Japanese and non-Japanese. The development strategy is to perform dose-response studies in both races, take two doses forward to phase III development in non-Japanese, and bridge the non-Japanese phase III data to Japan. The high dose is to be the Effective Dose (ED), which just exceeds the 50% LDL response in non-Japanese to be competitive with Lipitor. The low dose is the next lowest dose studied in non-Japanese, which is to be used if the high dose is not tolerated well. Left. Similar efficacy is defined to occur when both doses to take forward to Phase III in non-Japanese create a response that is within 5% of the response of the matching doses

27

in Japanese (large ovals). Right. Similar efficacy is defined to occur when the high dose is similar to the matching dose in Japanese (large oval), and the 90% confidence interval on the ratio of the slopes of the dose-response curves lies between 0.8 and 1.25.

References 1. Takeuchi, M. Statistical Issues on Bridging Studies. Kitasato University-Harvard School of Public Health Symposium on Global Drug Development Techniques: Bridging Strategies. Tokyo 2000. 2. Shih WJ. Clinical Trials for Drug Registrations in Asian-Pacific Countries: Proposal for a New Paradigm from a Statistical Perspective. Control Clin Trials 2001;22:357–366 2001 3. Goto M, Hamasaki T. Practical issues and observations on the use of foreign clinical data in drug development. J Biopharm Stat. 2002 Aug;12(3):369-84. 4. Chow SC, Shao J, Hu OY. Assessing sensitivity and similarity in bridging studies. J Biopharm Stat. 2002 Aug;12(3):385-400. 5. Liu JP, Chow SC. Bridging studies in clinical development. J Biopharm Stat. 2002 Aug;12(3):359-67.

28