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Statistical Work Experiences in a Major Pharmaceutical Company

Qiming Liao, Ph.D

Hui Zhi, Ph.D

GlaxoSmithKline Pharmaceuticals, R&D

Nov 4, 2011

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• 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

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A global Pharmaceutical Company (GSK as an example)

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• A Global Pharmaceutical Company (GSK as an A Global Pharmaceutical Company (GSK as an example) example)

• Overview of the Drug Discovery & Development Process

• The Statistician's Role in the R&DThe Statistician's Role in the R&D

Presentation Overview

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Key Steps in the Drug Discovery & Development Process

genes proteintargets

chemicaldiversity

identify‘hit’

optimize‘hit’ structure test safety/efficacy

animals humans

genomics combinatorialchemistry

high-throughputscreening

SAR

pharmacologyDMPK

toxicologychemical development

pharmaceutical development

clinical trials

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New Drug Development

Nonclinical

IND Submission

Clinical (Human)Phases I-III

NDA. Submission

Approval

Phase IV

Discovery

FTIM - PoC

Efficacy trialPost Approval Commitments

IND = Investigational New Drug NDA = New Drug Application

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Pre-clinical & Safety

Assessment

Clinical Pharmacology &

Phase I

Phase II Phase IV

Phase III

The Drug Development Puzzle

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Nonclinical ActivitiesPre-clinical & Safety Assessment

Drug DiscoveryGenomics, Combinatorial Chemistry, High-throughputScreening, Medicinal Chemistry, Follow-up Screening

Pre-clinical Drug DevelopmentPre-clinical Pharmacology, Drug Metabolism andPharmacokinetics, Animal Toxicology (SafetyAssessment)

Drug Product & Process DevelopmentChemical 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)

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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)

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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)

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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

Phase III

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Phase IV

• Post approval studies

• Regulatory requests

• New indications

• Improved formulations

• Publications

Phase IV

Clinical Trials (Phase IV)

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• A Global Pharmaceutical Company (GSK as an A Global Pharmaceutical Company (GSK as an example) example)

• Overview of the Drug Discovery & Development Overview of the Drug Discovery & Development ProcessProcess

• The Statistician's Role in the R&D

Presentation Overview

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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)

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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)

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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.

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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)

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Other Statistical Opportunities at GSK

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

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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

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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

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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

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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

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Equally Important - ‘Non-statistical’ Skills

Communication Negotiation Teamwork & Customer Focus Time Management Scientific Terminology Attending/Leading Meetings Making Technical Presentations Recruitment Leadership

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www.gsk.comwww.biometrics.com

Striving to make

people’s lives

healthier...

Preventing,

diagnosing and

curing disease

GlaxoSmithKline Pharmaceuticals