Statistical Work Experiences in a Major Pharmaceutical Company Qiming Liao, Ph.D Hui Zhi, Ph.D

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

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

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

7. Key Steps in the Drug Discovery & Development Process genes proteintargets chemicaldiversity identify‘hit’ optimize‘hit’ structure test safety/efficacy animals humans pharmacologyDMPKtoxicologychemical development pharmaceutical development clinical trials genomics combinatorialchemistry high-throughputscreening SAR

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

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

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

12. Phase II Clinical (Phase II) • 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!

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

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

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

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)lLearning - Keeping up with the science & technology. • Research (publications/presentations)

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

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

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

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

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

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

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

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

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