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
• 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
A global Pharmaceutical Company (GSK as an example)
4
5
6
• 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
7
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
8
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
9
Pre-clinical & Safety
Assessment
Clinical Pharmacology &
Phase I
Phase II Phase IV
Phase III
The Drug Development Puzzle
10
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)
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
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
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
14
Phase IV
• Post approval studies
• Regulatory requests
• New indications
• Improved formulations
• Publications
Phase IV
Clinical Trials (Phase IV)
15
• 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
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
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
Striving to make
people’s lives
healthier...
Preventing,
diagnosing and
curing disease
GlaxoSmithKline Pharmaceuticals