1. 1 Statistical Work Experiences in a Major Pharmaceutical Company Qiming Liao, Ph.D Hui Zhi, Ph.D GlaxoSmithKline Pharmaceuticals, R&D Nov 4, 2011

2. 2 A Global Pharmaceutical Company (GSK as an example) Overview of the Drug Discovery & Development Process The Statistician's Role in the R&D Presentation Overview

3. 3 A global Pharmaceutical Company (GSK as an example)

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6. 6 Presentation Overview

7. 7 Key Steps in the Drug Discovery & Development Process genes protein targets chemical diversity identify ‘hit’ optimize ‘hit’ structure test safety/efficacy animalshumans genomics combinatorial chemistry high-throughput screening SAR pharmacology DMPK toxicology chemical development pharmaceutical development clinical trials

8. 8 New Drug Development Nonclinical IND Submission Clinical (Human) Phases I-III NDA. Submission Approval Phase IV Discovery FTIM - PoC Efficacy trial Post Approval Commitments IND = Investigational New Drug NDA = New Drug Application

9. 9 Pre-clinical & Safety Assessment Clinical Pharmacology & Phase I Phase IIPhase IV Phase III The Drug Development Puzzle

10. 10 Nonclinical Activities Pre-clinical & Safety Assessment Drug Discovery Genomics, Combinatorial Chemistry, High-throughput Screening, Medicinal Chemistry, Follow-up Screening Pre-clinical Drug Development Pre-clinical Pharmacology, Drug Metabolism and Pharmacokinetics, Animal Toxicology (Safety Assessment) Drug Product & Process Development Chemical Development (active ingredient process development – synthetic/analytical chem) Pharmaceutical Development (develop final dosage form and process – tablets, inhaler, etc) Biopharm Development (cell culture, protein purification – biologically-based active ingred, including vaccines)

11. 11 Phase I (1-2 years) First time in humans (healthy volunteers) Safety and Tolerability Pharmacokinetics, Pharmacodynamics Drug-Interaction CP & Phase I Clinical Pharmacology (Phase I)

12. 12 Phase II (now PoC) (24 months) Safety Tolerability Dose Response for safety and efficacy Selection of Dose for Confirmatory Trials Prove using validated markers that compound works! Phase II Clinical (Phase II)

13. 13 Clinical Trials (Phase III) Phase III (24-36 months) n General patient population n Long Term, Large Studies n Confirmatory Efficacy for Registration n Risk:Benefit assessment and product labeling Phase III

14. 14 Phase IV Post approval studies Regulatory requests New indications Improved formulations Publications Phase IV Clinical Trials (Phase IV)

15. 15 Presentation Overview

16. 16 Statistician’s Role: Nonclinical Consulting - Statistical consulting in experimental design, data analysis, regulatory issues and report writing. - Statistical support to one or two client groups (e.g. Analytical Chemistry and Synthetic Chemistry) * Separate group for supporting Toxicology at GSK - Need to know basic concepts and jargon of client group’s discipline. (In pre-clinical the scientific details can take time to learn.) Training & Enablement - Provide specialized courses to those clients that need them. (e.g. basic biostatistical concepts, data visualization, factorial & fractional- factorial designs, key statistical software) Learning - Keeping up with the science & technology. Research (publications/presentations)

17. 17 Statistical Methods Frequently Used n Analysis of Variance/Covariance (including variance components estimation) (SAS PROC GLM, MIXED, NPAR1WAY) n Repeated measures and cross-over designs (SAS PROC GLM, MIXED, MULTTEST, GENMOD) n Factorial, Fractional Factorial, & Mixture Designs for Assay or Chemical Process Optimization (Design Expert, SAS PROC REG, GLM, CATMOD) n Linear & Nonlinear Regression for shelf-life calibration and drug potency calibration (SAS PROC REG, NLIN) n Multivariate Methods (principal components, PLS) (SIMCA, SAS, Statistica) n Graphics (SAS, S-plus, Statistica)

18. 18 Statistician’s Role: Clin. Pharmacology (I, IIa) & Clinical (IIb,III,IV) Project - Consulting (similar to Nonclinical) - Part of a team to handle a drug project - Provide input into the design of the experimental protocol - Provide data analysis and interpretation - Statistical representative on drug project meetings - Responsible for sign-off on the statistical aspects of the study - Defend study designs, analyses, and statistical interpretation of data to regulatory agencies. Non-project - “Lunchtime Learning” seminars to clinical customers. - Statistical research (publication/presentation) - In-licensing of new products from other companies.

19. 19 Statistical Methods Frequently Used n Analysis of Variance/Covariance (SAS GLM, MIXED) n Categorical Analysis (SAS CATMOD, FREQ) n Repeated Measures Analysis (SAS PROC MIXED) n Logistic Regression (SAS LOGISTIC) n Survival Analysis (SAS PHREG, LIFETEST) n PK/PD Modeling, NLMEM (SAS, S-plus) n Sample size determination (nQuery, PASS) n Graphics (S-plus, SAS, Statistica)

20. 20 Other Statistical Opportunities at GSK n Other Statistical groups at GSK Worldwide Epidemiology Discovery Analytics Research Statistics Unit Quantitative & Decision Sciences

21. 21 Support to Epidemiology n Design & Analysis of observational studies n Safety signal detection & interpretation of rare events n Understanding natural disease progression & risk benefit of therapies n Use of observational databases to design clinical trials

22. 22 Discovery Analytics n Use biomarker data to help progress compounds and position products n Develop novel patient classification models for clinical trial enrichment and prognostics n Build better cell-based and animal assays for improved progression decisions n Differentiate our products as early as possible by determining patient subpopulations and dosing regimens

23. 23 Research Statistics Unit n Develop new statistical methods, particularly in emerging scientific areas n Provide consultancy and advanced theoretical and computational expertise to statisticians and researchers throughout GSK n Promote, improve, and implement the application of advanced methods in design, modelling, and analysis

24. 24 Quantitative & Decision Sciences n Provide structured facilitation n Develop & apply tools and visualizations to illustrate trade-offs n Develop & apply analytical methodologies to business opportunities n Conduct analyses to identify & evaluate options n Develop & offer training in principles of decision analysis & risk assessment

25. 25 Equally Important - ‘Non-statistical’ Skills n Communication n Negotiation n Teamwork & Customer Focus n Time Management n Scientific Terminology n Attending/Leading Meetings n Making Technical Presentations n Recruitment n Leadership

26. 26 www.gsk.com www.biometrics.com Striving to make people’s lives healthier... Preventing, diagnosing and curing disease GlaxoSmithKline Pharmaceuticals