Clinical Data – Dealing with the Chips as they Fall

Patricia L. Ruppel, Ph.D.

President, dKb Technologies

2003 Spotfire User Conference

Boston, 28 October 2003

Paint the Picture

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

NDA

Study 989

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Oh No !!!!!!

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

PBO TRT

Results – Not Positive

Primary Outcome

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

SpotfireDecisionSite

CanHelp

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

High Failure Rate in Drug Development

Stage

10,000

250

10

1

Discovery

Preclinical

Clinical

FDA Approval

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Reasons why 90% of compoundsfail in clinical development

Lack of Efficacy

31%

ADME Properties

41%

Toxicity22%

Market/Comm

Reasons6%

Prentis et al, Br J Clin Pharm 1988

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

How Can Spotfire DecisionSite Help?

Rapid exploration through the data

Performed in team setting

Minimizes time and resources

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Case Study3-Arm Double-blind Controlled Study in 466 Depressed Patients

• Placebo control N=161 patients• Test compound N=151 patients• Active control N=154 patients

5 Investigative Sites

0

5

10

15

20

25

Baseline 21 Wks

PBO TEST ACTIVE

Ham-D Score

0

25

50

75

100

PBO TEST ACTIVE

%Pts Ham-D Responders

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Strategies for Exploring Results

Are there skewed / outlier data affecting results

• Correlation with other clinical endpoints

Are there site / investigator aberrations

Can efficacious subgroups be identified

• forward exploration

• backward exploration

Scatter Plot

trtactive pbo test

-15

-10

-5

0

5

10

15

20

25

30

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Scatter Plot of Ham-D Change from Baseline for each Treatment Group

Active Pbo Test

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

-120-100-80-60-40-20

020406080

100

active pbo testtrt

hdpchg

Box Plots of Ham-D Change from Baseline for each Treatment

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Scatter Plot

mdrschg-10 0 10 20 30 40

-15

-10

-5

0

5

10

15

20

25

30

Scatter Plot of Ham-D Change from Baseline vs. Madrs Change from Baseline

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Scatter Plot

inv

trt - active

trt - test

trt - pbo

1 2 3 4 5 1 2 3 4 5

-100

-75

-50

-25

0

25

50

75

100

-100

-75

-50

-25

0

25

50

75

100

Differences in Ham-D Response Across InvestigatorsActive Pbo

Test

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Pie Chart

trt

15

Non-Responder, 20%

Responder, 80%

33

Non-Responder, 33%

Responder, 67%

28

Non-Responder, 43%

Responder, 57%

34

Non-Responder, 32%

Responder, 68%

44

Non-Responder, 39%

Responder, 61%

22

Non-Responder, 77%

Responder, 23%

27

Non-Responder, 48%Responder, 52%

30

Non-Responder, 40%

Responder, 60%

38

Non-Responder, 32%

Responder, 68%

44

Non-Responder, 61%

Responder, 39%

15

Non-Responder, 33%

Responder, 67%

32

Non-Responder, 50%Responder, 50%

28

Non-Responder, 36%

Responder, 64%

34

Non-Responder, 41%

Responder, 59%

42

Non-Responder, 45%

Responder, 55%

active pbo test

1

2

3

4

5

Ham-D Response Rates across Treatments and Investigators

Active Pbo Test

Pie Chart

inv

52

Recurrent Episode, 73%

Single Episode, 27%

92

Recurrent Episode, 65%

Single Episode, 35%

86

Recurrent Episode, 71%

Single Episode, 29%

106

Recurrent Episode, 70%

Single Episode, 30%

130

Recurrent Episode, 78%

Single Episode, 22%

1 2 3 4 5

1

2

3

4

5

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Episode Rates across Investigators

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Data Quality vs. Quality of Response

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Pie Chart

trt

31

Non-Responder, 35%

Responder, 65%

43

Non-Responder, 47%

Responder, 53%

34

Non-Responder, 53%

Responder, 47%

47

Non-Responder, 38%

Responder, 62%

40

Non-Responder, 50%Responder, 50%

44

Non-Responder, 41%

Responder, 59%

32

Non-Responder, 44%

Responder, 56%

39

Non-Responder, 62%

Responder, 38%

35

Non-Responder, 40%

Responder, 60%

active pbo test

Absent

Definitelypresent

Probablypresent

Active Pbo Test

Ham-D Response Rate by Presence of Underlying Stress at Study Start

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Pie Chart

trt

110

Non-Responder, 35%

Responder, 65%

119

Non-Responder, 53%

Responder, 47%

106

Non-Responder, 43%

Responder, 57%

44

Non-Responder, 34%

Responder, 66%

42

Non-Responder, 43%

Responder, 57%

45

Non-Responder, 40%

Responder, 60%

active pbo test

Recurr...Episode

SingleEpisode

Ham-D Response Rate by Episode Recurrance

Active Pbo Test

Pie Chart

trt

36

Non-Responder, 39%

Responder, 61%

32

Non-Responder, 31%

Responder, 69%

37

Non-Responder, 27%

Responder, 73%

49

Non-Responder, 41%

Responder, 59%

40

Non-Responder, 53%

Responder, 48%

34

Non-Responder, 53%

Responder, 47%

33

Non-Responder, 45%

Responder, 55%

53

Non-Responder, 49%Responder, 51%

27

Non-Responder, 37%

Responder, 63%

38

Non-Responder, 42%

Responder, 58%

43

Non-Responder, 47%

Responder, 53%

41

Non-Responder, 44%

Responder, 56%

active pbo test

20-29

30-39

40+

<20

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Active Pbo Test

Ham-D Response Rate by Age of Onset

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Backward Approach

What differentiates responders vs non-responders

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Profile Chart hd21resp - Non-Responder

trt - active

hd21resp - Responder trt - active

hd21resp - Non-Responder trt - pbo

hd21resp - Responder trt - pbo

hd21resp - Non-Responder trt - test

hd21resp - Responder trt - test

age (normaliz...a... St...M... Li... E... ep... ag...a... St... M... Li... E... ep... ag...a... St... M... Li... E... epi...

-2

-1.5

-1

-0.5

0

0.5

1

1.5

2

2.5

-2

-1.5

-1

-0.5

0

0.5

1

1.5

2

2.5

Age of Onset

Ham-D Non-Responders

Ham-D Responders

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Age

Primary Splitters for Test Treatment Ham-D Responders

Episode Occupation

Age AgeOnset AgeLiving

Situation AgeOnset

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Primary Splitters for Placebo Treatment Ham-D Responders

AgeOnset

AgeOnset

AgeOnset

AgeOnsetAgeOnset

AgeSex

OccupationEpisode

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Treatment Separators are not Enough

0

25

50

75

100

0

25

50

75

100

0

25

50

75

100

Test

Test

Test

Pbo

Pbo

Pbo

All Patients

Subgroup 1

Subgroup 2

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

Separating Desirable Bins from Undesirable Bins

Test RespondersPbo Non-Responders

Test Non-RespondersPbo Responders

Focus is on “Active” Treatment Response

dKb Technologies 2003 Spotfire User Conference Boston, 28 October 2003

How Can Spotfire DecisionSite Help?

Rapid exploration through the data• run through all collected variables• univariately and mutivariately

Performed in team setting• different knowledge and perspectives from

members different avenues of exploration Minimizes time and resources

• also gives a deeper understanding of

therapeutic area / drug response• directions for future study designs