1 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 ASENT INTERNATIONAL SYMPOSIUM ~ Acceptability of Foreign Data~ February 26, 2011 February 26, 2011 Yoko Fujimoto MD PhD, Neurology, Development Japan, Pfizer Japan Inc. Global Clinical Development & Acceptance of Foreign Data in Japan

2 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Agenda 1. Looking back on the Past Decade 2 ． Recent Progress 2 ． Recent Progress 3. Challenges & Future Direction 3. Challenges & Future Direction Global Clinical Development & Acceptance of Foreign Data in Japan

3 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Full Development to Bridging Strategy Based on the adoption of the ICH E5 in 1998 US/EU filing US/EU Phase II Phase III Phase I Decision making Drug Lag J Phase II J Phase III J Phase I JAPAN Full Development :Local Studies Bridging Strategy Exporalation of Global Phase III Japan filing ~ Looking back on the past decade~ Drug Lag Japan filing J P2 Bridging StudyJ Phase I

4 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Significant Drug Lag in Japan 5 (6%) 9 (10%) 15 (17%) 2 (2%) 1 (1%) 9 (10%) USA UKGermany France Korea TaiwanHong Kong Japan Number of unapproved drugs in the world among the top 90 ranking drugs in (1%) 21 (23%) 35 (39%) in 2004 Source : News from Office of Pharmaceutical Industry Research (Think tank of JPMA) of July 2008 ~ Looking back on the past decade~

5 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Example in Neurology: anti-AD drug Significant drug lag existed in Japan ~ Looking back on the past decade~ NMDA inhibitor ChE inhibitor Drugs JAPAN US Donepezil (Aricept) Revastigumine oral Revastigumine patch Galantamine Memantine (Namenda) EU Approval Year ~3 years + 4 years + 10~11 years + 8~9 years

6 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Agenda 1. Looking back on the Past Decade 2 ． Recent Progress 2 ． Recent Progress 3. Challenges & Future Direction 3. Challenges & Future Direction Global Clinical Development & Acceptance of Foreign Data in Japan

7 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Development Strategies in Japan Full Development Full Development  Local Development Bridging Strategy Bridging Strategy Global Development Global Development  Multinational Trial  Asian Study Regulatory Guidance on Global Clinical Trials in 2007 ~ Looking back on the past decade~ ICH E5 in 1998

8 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Guidance: Basic Principles on Global Clinical Trials (1) Regulatory Guidance “Basic Principles on Global Clinical Trials” was issued by MHLW in 2007 Regulatory Guidance “Basic Principles on Global Clinical Trials” was issued by MHLW in 2007 Key Message of the guidance: Promote the conducting global clinical trials more appropriately with consideration of ethnic factors Key Message of the guidance: Promote the conducting global clinical trials more appropriately with consideration of ethnic factors ~ Recent progress~

9 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Guidance: Basic Principles on Global Clinical Trials (2) ~ Recent progress~ Q&A from Basic principles on global clinical trials (Sep. 28th 2007) 2. What is an appropriate timing for Japan to participate in global drug development? Regarding clinical developments that are globally proceeding, it is recommended to participate as soon as possible. Therefore, prior consideration is important so that, at the latest, participation to the exploratory dose-finding study could be possible.

10 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Guidance: Basic Principles on Global Clinical Trials (3) ~ Recent progress~ 3. Is it mandatory to have a phase 1 trial or pharmacokinetic information in Japanese population prior to conduct of a global clinical trial for patients? The dosage regimen to be used in the global trial should be confirmed beforehand as to whether it does not have any particular safety problem for the Japanese. Q&A from Basic principles on global clinical trials (Sep. 28th 2007) For this purpose, before the start of the global clinical trial, at least it is required to examine single dose safety and pharmacokinetics of investigational drugs in Japanese healthy volunteers or patients, compare the results with non Japanese, and confirm that risks in the Japanese are equivalent with non Japanese.

11 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Five Year Clinical Trial Activation Plan ~ Recent progress~ By MHLW since 2008 Goals of five year clinical trial activation plan   Reinforce clinical research infrastructure to ensure safe and secured patient’s access to new drug and devices – –Build nationwide infrastructure to perform innovative and valuable clinical research in a smooth manner – –Network core clinical research sites where research skills and resources are highly integrated Actions   Clinical study infrastructure building – –10 core clinical research centers and 30 major clinical trial institutions   Human resource development for clinical research – –Training provision for MDs, CRCs, Biostatisticians, Data managers etc   Public promotion of clinical trial and encouraging participation   Efficient clinical research management and sponsor’s ease

12 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Bridging Strategy to Global Development P2 Bridging study Phase I Drug Lag Phase II Phase III Phase I JAPAN Full Development Bridging Strategy Exporalation of Phase III Simultaneous filing Phase II Phase III Phase I Japanese patients in Global Phase ll/III Japan Phase I Global Development Japan filing ~ Recent progress~ US/EU

13 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 CLINICAL PHARMACOLOGY & THERAPEUTICS K. Ichimaru, S. Toyoshima, Y. Uyama ~ Recent progress~ Numbers and Percentages of Global Clinical Trials Numbers of clinical trial Numbers of Global trial Percentages of GCTs

14 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 ~ Recent progress~ Trends of Disease Field in Global Clinical Trials CLINICAL PHARMACOLOGY & THERAPEUTICS K. Ichimaru, S. Toyoshima, Y. Uyama

15 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Pfizer Japan Data As of March, 2010 Changes in Development Strategy Global Alignment in Pfizer Japan 69.7% Global Alignment Others Incl. EPBU All Projects Simultaneous filing strategy: within 6M from global filing (excluding post J-NDA projects) Copyright 2010 Pfizer Japan Inc. All rights reserved. Any reuse, distribution or alteration without express written permission of Pfizer Japan Inc. is prohibited. ~ Recent progress~ Primary Care BU Specialty Care BU Oncology Care BU 57.1% Others 80.0% Others 82.4% Others

16 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 ~ Recent progress~ Number of Global & Local Trial in Pfizer Japan Pfizer Japan Data As of March, 2010 Local Global

17 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Changes in Neurology: anti-AD drug Global Development is a current standard ~ Recent progress~ Phase IIa Global Phase IIb Phase I J Phase I Japanese patients; ~20% AD Disease modifying drugs; e.g. anti-Aβ antibody Phase IIa Phase III Phase I J Phase I Phase IIb AD symptomatic treatment; e.g. 5-HT inhibitor

18 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Agenda 1. Looking back on the past decade 2 ． Recent Progress 2 ． Recent Progress 3. Challenges & Future Direction 3. Challenges & Future Direction Global Clinical Development & Acceptance of Foreign Data in Japan

19 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Ethnic Difference  Extrinsic Factors: Medical practice, diet, exposure to pollution and sunshine etc.  Intrinsic Factors: Genetic polymorphism, weight etc. Challenges (1) ~ Challenges and Future Direction~

20 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Difference in Daily Doses between Japan and US The 1 st China-Korea-Japan Working Group ~ Challenges and Future Direction~ ・ Ethnic difference ・ Safety/ Tolerability ・ Japan Preference ・ MHLW/PMDA Why? Cardiovascular Others

21 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Ethnic Difference  Extrinsic Factors: Medical practice, diet, exposure to pollution and sunshine etc.  Intrinsic Factors: Genetic polymorphism, weight etc. Challenges (2) ~ Challenges and Future Direction~ Requirement for Sample Size of Japanese Patients Requirement for Sample Size of Japanese Patients

22 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Q&A from Basic principles on global clinical trials (Sep. 28th 2007) ~ Challenges and Future Direction~ Sample Size of Japanese Subjects (1) 6. When conducting an exploratory trial like a dose-finding study or a confirmatory trial as a global clinical trial, how is it appropriate to determine a sample size and a proportion of Japanese subjects? …. a sufficient statistical power to detect statistically significant difference should not necessarily be secured within the Japanese subpopulation. However, when the entire study population across regions is defined as a primary analysis population in a confirmatory study, the justification should be explained as to why the entire population can be deemed as one population, while each regional population is not used.

23 ACI Life Sciences Mergers & Acquisitions – March 12, % of Japanese are required for registration trial at the minimum Issues on sub-analysis still remain to be discussed 10-20% of Japanese are required for registration trial at the minimum Issues on sub-analysis still remain to be discussed ~ Challenges and Future Direction~ Sample Size of Japanese Subjects (2) – –Kawai, N et al, An Approach to Rationalize Partitioning Sample Size Into Individual Regions in a Multi-regional Trial, Drug Info. J. 42, (2008) – –Quan, H et al, Sample size considerations for Japanese patients in a multi- regional trial based on MHLW guidance. Pharmaceut. Statist. Published Online: Jun :09AM /pst.380 (2009). A global trial should be designed as that consistency can be obtained between results from the entire population and the Japanese population, A global trial should be designed as that consistency can be obtained between results from the entire population and the Japanese population, and by ensuring consistency of each region, it could be possible to appropriately extrapolate the result of full population to each region. To consider the possibility to obtain consistent results between the entire population and the Japanese population when designing a global trial, the following methods can be applied; To consider the possibility to obtain consistent results between the entire population and the Japanese population when designing a global trial, the following methods can be applied;

24 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Ethnic Difference Ethnic Difference  Extrinsic Factors: Medical practice, diet, exposure to pollution and sunshine etc.  Intrinsic Factors: Genetic polymorphism, weight etc. Requirement for Sample Size of Japanese Patients Requirement for Sample Size of Japanese Patients Challenges (2) ~ Challenges and Future Direction~ Other Japan Specific Requirements Other Japan Specific Requirements  Bioequivalence (BE) Data –May require independent BE study only for Japan, due to differences in assessment methods between Japan and West  Additional information is required for CTD in Japanese

25 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Establish an efficient way to handle ethnic differences in global studies Establish an efficient way to handle ethnic differences in global studies Collaboration with Asian countries Collaboration with Asian countries Close Alliances among FDA, EMA & PMDA (Asia) Close Alliances among FDA, EMA & PMDA (Asia) Future Direction ~ Challenges and Future Direction~

26 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 Thank you !

27 ACI Life Sciences Mergers & Acquisitions – March 12, 2009 No.3: Failure of Clinical trial in Japan (Pharm Industry/ Investigational Site) Background of Approval Delay in AD Drugs Development Underlying issue of AD clinical trial Poor infrastructure for clinical trial in Japan No.2: Hesitation to initiate clinical trial in Japan (Pharm Industry) Long Review Period Requirement of Japanese data No.1: High Demand of Regulatory Agency （ PMDA/MHLW) ~ Looking back on the past decade~