Statistical and Graphical Analysis of Adverse Event Counts in ...

Floor Discussion 3:45 PM

Design of Statistical Graphics for Clinical Data Richard M. Heiberger, Temple University

3:25 PM

Graphical Analyses of Clinical Trial Safety Data Haijun Ma, Amgen Inc.; Kefei Zhou, Amgen Inc.; Hong A. Xia, Amgen Inc.; Matthew Austin, Amgen Inc.; George Li, Amgen Inc.; Michael O'Connell, InsightfulCorporation

3:05 PM

Statistical Graphics for the Analysis of Safety and Efficacy Data from Clinical Trials William Bushnell, GlaxoSmithKline

2:45 PM

Using Graphics To Discover and Explore Julia Wang, Johnson & Johnson PRD

2:25 PM

Statistical Graphics for Analysis and Reporting of Clinical Trials Michael O'Connell, Insightful Corporation

2:05 PM

Chair(s): Stephen Kaluzny, Insightful Corporation

Organizer(s): Michael O'Connell, Insightful Corporation

Section on Statistical Graphics, Section on Risk Analysis, WNAR

Statistical Graphics for Analysis of Drug Safety and Efficacy

Todays AgendaTodays Session

www.splus.mathsoft.com 2Copyright ©1999-2007Insightful Corporation. All Rights Reserved. 2

Todays Session

Michael O’Connell+ Statistical Graphics Principles – Functional Areas, Software

Julia Wang + Graphs for Exploratory Data Analysis

William Bushnell+ Graphs for Safety - Labs, AEs, patient profile, …

Haijun Ma + Graphs for Safety - Labs, AEs, patient profile, …

Rich Heiberger+ Graphs / Design for Vitals, Labs, AEs, …

Copyright ©1999-2007Insightful Corporation. All Rights Reserved.

Statistical Graphics for Analysis and Reporting of Clinical Data

Michael O’Connell

July, 2007


My Outline

Business Problem+ Clinical Drug Development – Use of Graphics

Statistical Graphics + Graphics Principles, Elements, Types and Patterns

Graphics in Functional Areas+ Design, Review, Report

Software+ Graphics breakdown and mashup

First inHuman

Proof of Concept Confirmation Marketing

NDA FilingLSSS ?

IND Filing

End of Phase 2 Mtg

Drug Development

Healthy VolunteerSafety ADME

Diseased PatientDosingM & S

Real WorldOutcomes

Epidemiology

Large PopulationSafety

Efficacy

Clinical Drug Development

Candidate Selection

Phase I Phase II Phase III Phase IVPre-Clinical

Compound EvaluationPharmaceutic /

Chemical Development

FDA

–Pha

rma I

nter

actio

nsPh

arm

a Mile

ston

es

Need to go faster, better/safer and cheaper !! [$1B/yr drug = $3M/day]

Monitors

Data Mgt

Clinical

Statistics

Statistics

Programming

Publishing

Medical Writing

Clinical Trial Environment – Use Cases, Actors

Instream Unblinded

Statistics

Clinical

Management

ProtocolSAP

DataCleaning

Safety InstreamClinicalReview

CSRNDA

Labeling

JournalsScientific Meetings

Trial Design EDA / Review Report: Submission, Publication

Design


Statistical Graphics drive faster and better decisions

Speed the analysis and reporting process+ Faster registrational documents

Improve the quality of decisions+ Rapid and clear information from data

Increase likelihood of discerning safety and efficacy signals+ Comparative graphical analysis on all safety and efficacy data

Provide consistent form of communication across organization, cultures and functional areas

Improve interactions between sponsors and FDA+ FDA wants transparency and clear analysis / presentation

Statistical Graphics Value


Tufte’s Principles

+ Show all the data when possible

• Multivariate data and metadata+ Induce the viewer to think about the substance rather than the

graphic design – maximize the data-to-ink ratio+ Encourage the eye to compare different pieces of data – leverage

reader’s investment by showing multiple plots of same type

+ Reveal the data at several levels of detail, from a broad overview to the fine structure

+ Serve a clear purpose: description, exploration, tabulation+ Be closely integrated with the statistical and verbal descriptions of a

data set+ Use gray scale and color sparingly

Excellence in statistical graphics consists of complex ideas communicated with clarity, precision and efficiency

Statistical Graphics Principles


Variable Grouping+ Symbols, colors for groups – compare pieces of data

+ Treatment v Placebo

Trellis Plots and Conditioning + Panels for subjects, sub-groups – principle of small multiples

+ Adverse Event groups

Matrix Plots + Plots for individual variables together – multivariate data

+ Lab panels

Metadata – Margins and Axes+ Use of ticks, color-regions, margins around plots – multivariate metadata

+ Safety and Efficacy combination graphics

Brushing, Drilldown+ Data browsing – levels of detail

+ Population Lab -> Subject Lab -> AE -> demographics

Statistical Graphics – Functional Elements


Summary stats – univariate categorical + Dotplot+ Barchart [low data-to-ink ratio]+ Pie chart [poor perception]

Distributions – univariate continuous+ Boxplot+ Empirical CDF+ Density Plot+ Histogram

Relations and trends+ Line plot+ Scatter plot+ Scatter plot matrix+ Surface, contour and image (heatmap) plots

Basic Graph Types

+ Forest Plot

+ Kaplan Meier Plot


Figures convey trial designs and expected trial behavior+ Data analyst produces for clinician and management+ Multiple trial options are compared – operations (e.g. accrual) and

potential outcomes for variety of scenarios

Examples+ Protocol + SAP

Color and Format + Needs to be clear and easy to interpret and compare designs+ Statistical (e.g. # events) and calendar information need to be clearly

communicated

Illustrate today with survival trials

Trial Design Graphic

Trial Design Graphic: Sequential HR DesignLine Plot | Group Design

0.4

0.6

0.8

1.0

0 100 200 300 400 500 600

Number of Events

haza

rd ra

tiodsnA11Fixed

Futility boundary(Pocock)

Efficacy boundary(O’Brien-Fleming)

Superiority of Treatment

Inferiority of Treatment

H0: HR > 1H1: HR < 0.7

Trial Design Graphic: Sequential HR Design Line Plot | Group Design

Calendar Time

Num

ber o

f Sub

ject

s

0 10 20 30 40 50

020

040

060

0NAccrual= 700 Accrual Rate= 25.6 Accrual Time= 27.3 Study Time= 48.3

AccruedEventsAt Risk

HR= 0.7HR= 1

Accrual

Events

At Risk

(Months)

Interim Analyses

5 15 25 35 45 55 65 75 85 95 105 115 125 135 145

0.0

0.1

0.2

0.3

Sample Size

Distribution of Efficacy Boundary Crossing

Z (E

ffici

ent S

core

)

-4

-2

0

2

4

6

8

10 Fixed-Sample Size

Design Parameters:Simulation runs = 100000α = 0.05Power = 0.8

Simulation Results:P(cross upper boundary) = 0.93712P(cross lower boundary) = 0.06288

Mean sample size = 54.62555Median sample size = 50

Superiority

Inferiority

Futility

Trial Design Graphic: Adaptive DesignDesign Line Plot | Matrix

Courtesy Kye Gilder, Biogen


Figure not necessarily self-contained+ Data analyst produces for detailed review with clinician+ Data analyst produces for the data analyst

Examples+ Clinical data review by/with clinician+ Viewing all data – data cleaning

+ Residual diagnostics - identification of functional form of relationship, assessing model assumptions

Color and Format + Few pre-defined rules + Just make it clear and easy to interpret

Exploratory / Review Graphic


Adverse Events - Interpretive GoalsWhich adverse events are elevated in treatment vs. placebo?

How rapid is onset in treatment vs. placebo?

Population level analysis is important

Labs - Interpretive GoalsWhich subjects have elevated (liver) labs?

Are there subjects with elevation on multiple labs?

Subject Level analysis is important

Adverse Events

Adverse Events with Severity and Time

Data Courtesy Mat Soukup, FDA

Adverse Event Review Graphic

ReviewLine Plot | Group, Trellis

PT SOC TRT.A/214 TRT.B/428Abdominal distension Gastrointestinal disorder 5 0Abdominal pain Gastrointestinal disorder 11 11Abdominal pain lower Gastrointestinal disorder 2 0Abdominal pain upper Gastrointestinal disorder 5 2Acne Skin and subcutaneous tis 2 7 Ageusia Nervous system disorders 2 1 Alanine aminotransferase Investigations 8 22Alopecia Skin and subcutaneous tis 4 4Anaemia Blood and lymphatic syste 5 1Anorexia Metabolism and nutrition 9 10Anxiety Psychiatric disorders 4 3Arthralgia Musculoskeletal and conne 9 8Aspartate aminotransfera Investigations 32 3Asthenia General disorders and adm 7 2Back pain Musculoskeletal and conne 5 3Blood alkaline phosphata Investigations 3 1Blood creatinine increas Investigations 3 0Burning sensation Nervous system disorders 2 2Cancer pain Neoplasms benign, maligna 3 2Chest pain General disorders and adm 1 1Chills General disorders and adm 7 0... ... ... ... ... ...

Data Courtesy Mike Durante, GSK

Adverse Events Counts

ReviewScatter / pRisk Plot | Brush, Drill

Adverse Event Review Graphic: B&B Model

B&B Model: θij ~ πi I{0} + (1–πi) N(μθi, σθi2)

Insightful Clinical Review


Figure must be self-contained+ In-text figures should have an explanation in the caption

Figure must be documented+ Log file+ Time stamp+ Source data and output file references

Examples+ NDA Submission+ Scientific Publication+ Clinical Study Report and Presentation

Color / Format+ Must be interpretable when copied in black and white+ Compatible with Microsoft Word + Resizable

Report Graphic

DepressionDyspnoea.exertionalHepatic.function.abn

Pain.in.jawPyrexia

Skin.hypopigmentatioAnaemia

ParaesthesiaHair.texture.abnorma

HypotrichosisPharyngolaryngeal.pa

CystitisDysphonia

HyperbilirubinaemiaDry.mouth

Visual.acuity.reducePain.in.extremity

HypokalaemiaUrinary.tract.infect

DysgeusiaHeadache

Aspartate.aminotransHypertension

Fatigue

0 5 10 15 20 25 30

Protocol: 38-316 Page 1 of 1Candidate: Oncology 38-316-001

AE Dotplot: Percent by PT

Run: M O'ConnellTime: March 21, 2007; 10.06pm ETData Source: H:/Oncology/P38316/Report1/AEterm.sas7bdatOutput: H:/Oncology/P38316/Report1/AEterm.pdf

Percent

Trt.ATrt.B

Adverse Event Report GraphicReportDot Plot | Group

EpistaxisGastrooesophageal.reflux.disease

Pain.in.extremityMouth.ulceration

DysphoniaUrinary.tract.infection

Oedema.peripheralSkin.hypopigmentation

ConstipationParaesthesia

ChillsHeadache

Confusional.stateDysgeusia

Aspartate.aminotransferase.increasedPain.in.jaw

Skin.depigmentationHyperbilirubinaemia

Abdominal.distensionHypertension

Dry.mouthNausea

HypokalaemiaFatigue

2 4 6 8

Protocol: 38-316 Page 1 of 1Candidate: Oncology 38-316-001

Dotplot of Variable ImportanceRandom Forest Inside-Out Model

Run: M O'ConnellTime: March 27, 9.04pmData Source: H:/Oncology/P3816/Report/AEterm.sas7bdat

Variable Importance

Pre

ferre

d Te

rmAdverse Event Report Graphic

ReportDot Plot | Group

Trtij = f (PTj) + eij

i = 1, …, 642 subjects, j = 1, …, 111 AEs


Easy creation of (information-rich) statistical graphics for clinical data analysis

+ Dot plot, box plot, line plot, etc…

Easy re-purposing of graphs across studies and functional areas+ Graph standards – layering on (CDISC) data standards

Use of same graphs in exploratory and validated areas + Windows/UNIX exploratory and UNIX compliant

Consistent use of graphs across organization + Graphic language for effective communication

Key Use CasesSoftware Requirements

Monitors

Data Mgt

Apply Patternto Data

Clinical

Statistics

Apply Patternto Bound Data

Statistics

Programming

Run Bound Pattern

for NDA

Publishing

Apply CSS Style to

Bound Pattern

Graphics System Mashup

Instream Unblinded

Design Review Report

PersistedPersistedGraph Types, Graph Types,

Patterns, Styles & Patterns, Styles & MetadataMetadata

(WEBDAV)(WEBDAV)

SS--PLUS PLUS Script FilesScript Files

(SSC)(SSC)

Clinical Graphics Store

Statistics

Specify GraphFrom Type Palette

Create/Add Graph Pattern to Store

Select Graph Pattern from Store

Add Type to Palette


Summary stats – univariate categorical + Dotplot+ Barchart [low data-to-ink ratio]+ Pie chart [poor perception]

Distributions – univariate continuous+ Boxplot+ Empirical CDF+ Density Plot+ Histogram

Relations and trends+ Line plot + Scatter plot+ Scatter plot matrix+ Surface, contour and image plots

Graph Types and Patterns

+ Forest Plot+ My AE Dotplot with Intervals

+ My Boxplot

+ Kaplan Meier Plot+ My Patient Profile Liver Plot+ My Liver Lab Shift Plot+ My Liver Lab Scatter Plot Matrix

Graph Types Graph Patterns

Prostinol Phase III - Insightful Fuji SystemProstinol Phase III - Insightful Fuji System

File Edit View Insert Format Graph Data Window Help

New Graph...

Data Annotation History Metadata

Find Graphs... Saved GraphsImport Graphs...

Arial 12pt.

Saved Graphs

My most recent

All

LFT_ScatterPlotMatrix

Sort by:

Show:

AE_by_SOC_DotPlot

Base_2_End_LinePlot

Heart_Rate_LinePlot

Hemo_from_Base_LinePlot

Time_2_Response_KM

Discontinue_KM

Diaried_Change_BarPlot

Open Send to...

New Graph – Graph TypeNew Graph – Graph Type

Cancel

Line PlotKaplan MeierBar ChartScatter Plot Empirical CDFDot PlotHistogramPie ChartQQ PlotBox PlotForest Plot

My Recent All Graphs

Base Dot PlotDot Plot with IntervalAE Incidence Double Dot PlotAE Relative Risk Dot PlotAE Incidence and Relative Risk Dot Plot

Dot Plot with Interval

Data Source >

Graph Type

View by:

< Previous

Start with Graph Type

Start with Data Source

Selected Theme:CSR

Themes...

Dot Plot

Dot Plot with Interval(Preview)

Software Interface

vanHeerden (n = 9)

Trazzera (n = 18)

Tennenberg (n = 15)

Ramsay (n = 27)

Maki (n = 24)

Heard (n = 27)

Hannan (n = 17)

George (n = 12)

Combined (n = 61)

Collins (n = 8)

Ciresi (n = 17)

Bach(b) (n = 8)

Bach(a) (n = NaN)

-4 -3 -2 -1 0

logOR

nam

es

Page 1 of 1

Software Interface

DiarrhoeaDyspepsia

NauseaStomatitis

Gastrointestinal painVomiting

Haemorrhoidal haemorrhageLarge intestine perforation

ProctitisFlatulence

Abdominal painAbdominal pain lower

ToothacheGastric disorder

Gastrooesophageal reflux diseaseAbdominal pain upper

GlossitisMouth ulceration

ConstipationAbdominal distension

Dry mouth

-0.5 0.0 0.5 1.0

|||

|||

||||

|||||

|||||

|

log-10 Empirical RR Bayes Posterior Mean of Log Relative Risk with 99% BCI

Dot Plot Review

My AE Dot Plot with Interval Pattern

0.0

0.1

0.2

0.3

0.4

-2 0 2 4

Placebo 0.25mg

0.5mg

0.0

0.1

0.2

0.3

0.4

-2 0 2 4

1.0mg

Page 1 of 1

x

Freq

uenc

yHistogram | Trellis Report

My Histogram for Internal Power Point Pattern

0.00.10.20.30.4

-2 0 2 4

Placebo0.00.10.20.30.4

0.25mg0.00.10.20.30.4

0.5mg0.00.10.20.30.4

1.0mg

Page 1 of 1

x

Freq

uenc

y

Histogram | Trellis Report

My Histogram for Internal Power Point Pattern

Combined Graphical and Tabular Reports

Treatment Minus Placebo Stain at Week 4

Body Plot Review

Insightful Clinical Review

Futures: Interactive Clinical Review on the iPhone

Interactive Clinical Review on the iPhone


Point-click specification of statistical graphics (stats, programming)+ Easy to create informative statistical graphics (point-click)+ Comprehensive palette of graph types: dot plot, box plot, line plot, …

Create / save a graph pattern for re-use on bound or new data+ Instream clinical data review / cleaning (data refresh)+ Analysis of different trial/endpoint by different person/TA (CDISC helps)

System creation of script to be run in validated environment+ Oracle / SAS and submission reporting

Graph styling and presentation with bound data (publishing)+ Graph in to company power point style e.g. b&w <-> color+ Graph in to journal style + No change to scientific graph content

Create / add new graph type (stats)+ New statistical graphics added by statistics for use throughout

Permissioned re-purposing of complex statistical graphics

Key Use CasesKey Clinical Graphics Use Cases – Mashups

Insightful Services Oriented Architecture

XML Graph

Definition

S-PLUS Enterprise Server

PersistedGraph Patterns,

Styles & Metadata(WEBDAV)

S-PLUS Script File

(SSC)

Clinical Data

SAS Oracle CDISC EDC Safety

Graph View File

(SPJ)

SPJWMFPDFLOG

Libraries XSL GOM Libraries

SAS / S-PLUSMacros

SAS Engine

TOM

Create/Edit GraphPublish PatternRetrieve Pattern

S-PLUS Production Job Submit

SAS Production Job Submit

Graph View - UI Hooks -

S-PLUS Web / .Net ClientWeb Job Client

ODSLOGWMFPDF

CSS

SPJWMFPDF

XML Protocol

Define.xml

Insightful Clinical Graphics


Statistical Graphics are at the core in the analysis and interpretation of clinical / safety data

+ Comparative analysis of treatment effects+ Exploratory – understand the data, cleaning and outliers+ Review – all components of population and patient level data+ Submission – clinical study reports + Presentation – scientific and marketing applications

Consistency in statistical graphics principles/standards is key+ S-PLUS TrellisTM and S-PLUS GraphletsTM provide consistency across

graph types and environments + Same graphs in reports and exploratory data browsing+ Graphical language across organizations and industry

This is widely recognized by industry and the FDA

Vision for Statistical Graphics


Statistical Graphics are widely used to anchor the messaging from clinical studies

+ Group and Trellis / Metadata / Drill-down

Statistical Graphics are mashed up within pharma companies for rapid design, analysis, review, submission, publication and presentation

+ Using the clinical graphics taxonomy – types and patterns

A standard Statistical Graphics palette with rich APIs for repurposing is used across industry and the FDA

+ Simple interactions between industry and the FDA

In the not too distant future…… I see a world where

Safety and the critical path are making this reality

Vision for Statistical Graphics

Michael O’Connell moconnell@insightful .com

Today’s presentation will be available on our website soonhttp://www.insightful.com/news_events

Insightful’s 10th User Conference in Atlantic CityInsightful Impact 2007

October 10-11, 2007, Tropicana Hotel, Atlantic Cityhttp://www.insightful.com/news_events/impact2007/default.asp

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Statistical and Graphical Analysis of Adverse Event Counts in ...

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