The 2 nd Clinical Data Management Training Innovative Drug Research and Development ( 创新药品的研发过程） Frank Shen （沈志华）, Ph.D. Head of Biometrics and Clinical Management 生物统计数据和临床管理负责人 罗氏药品开发中国中心 August 30, 2010

2 My Objective is …  The Global Innovative Pharmaceutical Industry  The Complexity of Drug Development and Clinical Research  The Role of Data Manager played in Clinical Research  Challenges and Opportunities in China After this talk, you will have some good understandings about:

3 Top Line, Bottom Line, Pipeline and Regulated Industry

4 Drug Discovery to Drug Development: A Ten-Year Bet

5 Drug Discovery: Finding A Right Target and Picking Winners Identify a disease target: Cell Biology Genomics Mass-screening for hits: High-Throughput Screening (HTS) Miniaturization Identify a key: Combinatorial chemistry Natural Products Compound Acquisition Quantitative-Structure Activity Relationship (QSAR)

6 Early Phase Development: Use Clinical Pharmacology (CP), Pharmacokinetics (PK) and Pharmacodynamics (PD) to find A Right Drug  PK: What the body does to the drug  PD: What the drug does to the body AUC Cmax Tmax Drug Exposure (DOSE) Response (Effect) Max Effect 50% Effect 50% Effect Dose

7 Process Development Formulation/Stability File IND Phase IPhase II Clinical Trials Phase III File NDA APPROVALAPPROVAL Metabolism Toxicology Late Phase Development: Finding A Right Clinical Plan Drug Discovery Preclinical (II-B)(II A)

8 “If it were not for the great variability among individuals, “ If it were not for the great variability among individuals, medicine might as well be a science and not an art”

9 Dilemmas in Modern Medicine “Every day, doctors diagnose patients and prescribe the most appropriate drug, and yet in many cases, the drug won’t work or will trigger miserable side effects” - The Wall Street Journal

10 Relative signal/noise in drug studies due to inter-subject variability (noise) Phase 1 Phase 2 Phase 3

11 Evidence-Based Medicine is a Statistical-Based Medicine Population sample Inferences based on the sample Extrapolate e.g. patients with high cholesterol e.g. 150 patients with high cholesterol in a clinical trial e.g. statin reduces cholesterol

12 Hypothesis (Scientific belief) Data Collection Data Analysis Interpretation Confirm/Reject Refine Design of Scientific Experiments (e.g., Clinical Trial) Objective (Signals/endpoints)

13 Clinical Trials of New Drugs  A high-noise/low yield endeavor  Requires great care in design and execution for success  Expectations often not realized  50% of phase III trials failed to show positive results  Investment needs to be protected Buy A Good Insurance Policy and Execute with High Quality

14 Four Elements of Clinical Research Data and Monitoring Patient Protocol Biostatistics

15 Protocol Design Study Setup & Conduct Data Base Lock Analysis & Report Draft/Design Review CRF/Form Design Signoff FPFV Database design & verification LPLV CRF Lock Data Review, Query & Cleaning Clinical Trial and Protocol Life STAGE TASK Data Entry/ CRF Processing Data Q&R External Data Statistical Analysis Plan Data Review Plan Data Presentation Plan Medical Encoding Clinician/StatisticianCRA/DM Statistician/Clinician DM/CRA/Clinician Roles

16 Drug Development in China  Due to the large volume of generics, regulators (sFDA) concentrate mostly on drug manufacturing quality  Minimal experience in true innovation-based R&D processes  Complex regulatory processes subject to frequent policy changes and political environment 2005 US FDA Chinese sFDA # of New Drugs 201,113* # of Generics 3448,075 # of Reviewers 1, * Include formulation changes

17 Preclinical Phase I Phase IIIPhase II Marketing Authorization Global CTA Clinical TrialIDP Chinese Launch in China years CPP 4 years behind! Routine Registration Map in China (Imported Drugs)

18 China’s Rapid Pharmaceutical Market Growth Source: IMS Audit China Hospital Market 2010 Projected to be 3 rd largest market by 2013, 2 nd largest by 2020 CAGR +20% 2002 to 2011 driven by generics, branded generics and innovative medicines 18

19 There will be an increasing need for new medicines in China Changing Demographics in China (166M)(342M)

20 Great Opportunities for Professional Growth Come From 1.Outsourcing strategy from global companies and CRO to support global projects 2.R&D center from global companies focused on penetrating China ’ s high potential market 3.New Professions: Biostatistics, Programming (SAS and DBA), Data Management, Pharmacometrics, etc …

21 We Innovate Healthcare

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