1. 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. 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. 3 Top Line, Bottom Line, Pipeline and Regulated Industry

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

5. 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. 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. 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. 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. 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. 10 Relative signal/noise in drug studies due to inter-subject variability (noise) Phase 1 Phase 2 Phase 3

11. 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. 12 Hypothesis (Scientific belief) Data Collection Data Analysis Interpretation Confirm/Reject Refine Design of Scientific Experiments (e.g., Clinical Trial) Objective (Signals/endpoints)

13. 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. 14 Four Elements of Clinical Research Data and Monitoring Patient Protocol Biostatistics

15. 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. 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 1,800120 * Include formulation changes

17. 17 Preclinical Phase I Phase IIIPhase II Marketing Authorization Global CTA Clinical TrialIDP Chinese Launch in China 0 1 2 3 4 years CPP 4 years behind! Routine Registration Map in China (Imported Drugs)

18. 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. 19 There will be an increasing need for new medicines in China Changing Demographics in China 1995 - 2030 199520102030 19 (166M)(342M)

20. 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. 21 We Innovate Healthcare

22. The 2 nd Clinical Data Management Training Click to edit company slogan.