Robert GordonFDA/QSPI Biostatistics, Statistical Programming and Data Management SummitWashington D.C.March 2012

The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to any organization with which the presenter is employed or affiliated.

These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved.

2

Motivation behind the use of graphics Methodology across the sub teams Labs and Liver categories, clinical questions and

graphics Some examples Q & A

3

4

Mean of Y's 7.5

Mean of X's 9

Regression line Y = 0.5X + 3

5

6

7

Aid in identification of the unexpected Numerical quantities focus on expected values, graphical

summaries on unexpected values. (John Tukey) Identify patterns within the clinical data

Temporal, dose groups, demographics Combination of multiple lab parameters

Shift tables → matrix plots Identification of syndromes, concurrent abnormalities

Much more effective interpretation of tabular data Very large datasets

8

Identify the clinical questions that we are trying to answer regarding labs and liver results

Align appropriate graphs with their ‘most’ appropriate category – multiple crossovers

Critique and enhance graphs to best answer the questions

Consolidated questions and graphs to a concise set Provide background, uses, enhancements, and yes –

CODE! Upload to Wiki environment

9

10

Baseline & Trending Association between Lab Variables Liver Function Tests Graphs that aid in Determining

Emerging Safety Signals

11

What are the changes and percent changes from baseline over time? ie, are abnormal lab values a result of an abnormal baseline or have values changed on study?

Is there a temporal relationship between treatment and lab values?

What are the toxicity grade trends over time? What is the patient’s profile over time?

12

What is the association between lab assessments? Are there multiple lab values that are elevated or abnormal,

either concurrently or not? ie, how can we easily identify patients with simultaneous elevations in multiple lab tests over time?

13

How do we perform a comprehensive assessment of hepato-toxicity so that possible cases of drug induced liver injury are efficiently identified?

14

15

16

Subject ID Peak ALT ULN Peak Bili ULN Treatment

Subject 10013 5.65 0.74 ActiveSubject 10014 3.56 0.80 ActiveSubject 10015 2.73 1.13 ActiveSubject 10016 5.66 4.57 ActiveSubject 10017 2.47 0.88 ActiveSubject 10018 7.73 1.32 ControlSubject 10019 33.06 1.46 ActiveSubject 10020 11.60 3.23 ActiveSubject 10021 6.04 0.69 ControlSubject 10022 13.60 0.83 ActiveSubject 10023 1.85 0.58 ControlSubject 10024 0.21 0.42 ActiveSubject 10025 53.06 1.29 ActiveSubject 10026 8.36 1.63 ActiveSubject 10027 25.67 1.93 ActiveSubject 10028 31.23 1.27 Active

ACTIVE TREATMENT GROUP  Peak Bilirubin < 2 Peak Bilirubin ≥ 2 TotalPeak ALT < 3 1109 (73%) 29 (2%) 1138 (75%)Peak ALT ≥ 3 347 (23%) 30 (2%) 377 (25%)Total 1456 (96%) 59 (4 %) 1517 (100%)

CONTROL GROUP  Peak Bilirubin < 2 Peak Bilirubin ≥ 2 TotalPeak ALT < 3 579 (80%) 6 (<1%) 585 (81%)Peak ALT ≥ 3 128 (18%) 5 (<1%) 133 (19%)Total 707 (98%) 11 (2%) 718 (100%^)

17

18

How do we perform a comprehensive assessment of hepato-toxicity so that possible cases of drug induced liver injury are efficiently identified?

Subject 2001

Subject 2008

Subject 2035

19

SubjectID LabTest StudyDay xULNSubject 123456US ALT (SGPT) 0 0.8Subject 123456US ALT (SGPT) 8 0.6Subject 123456US ALT (SGPT) 14 6Subject 123456US ALT (SGPT) 18 3.3Subject 123456US ALT (SGPT) 29 3Subject 123456US ALT (SGPT) 33 5.2Subject 123456US ALT (SGPT) 36 2.5Subject 123456US ALT (SGPT) 40 1.9Subject 123456US ALT (SGPT) 44 1.8Subject 123456US ALT (SGPT) 48 2.8Subject 123456US ALT (SGPT) 52 1.2Subject 123456US ALT (SGPT) 54 1Subject 123456US ALT (SGPT) 56 1.2Subject 123456US ALT (SGPT) 59 0.8Subject 123456US ALT (SGPT) 64 1.5Subject 123456US ALT (SGPT) 70 1.4Subject 123456US AST (SGOT) 0 1Subject 123456US AST (SGOT) 8 0.9Subject 123456US AST (SGOT) 14 3.5

Study Day Treatment ALT (xULN) AST (xULN) Bilirubin (xULN)

0   0.8 1 0.88 X 0.6 0.9 0.6

14   6 3.5 218   3.3 2.8 0.829 X 3 1.4 0.733   5.2 2.5 1.136   2.5 1.8 0.640   1.9 1.6 0.744 X 1.8 1.6 0.848   2.8 1.8 0.952   1.2 1.2 0.854   1 1.3 0.956   1.2 1 0.859 X 0.8 1 0.864   1.5 1.3 0.670   1.4 1.2 0.4

  STUDY DAY  0 8 14 18 29 33 36 40 44 48 52 54 56 59 64 70Treatment   X     X       X         X    ALT (xULN) 0.8 0.6 6 3.3 3 5.2 2.5 1.9 1.8 2.8 1.2 1 1.2 0.8 1.5 1.4AST (xULN) 1 0.9 3.5 2.8 1.4 2.5 1.8 1.6 1.6 1.8 1.2 1.3 1 1 1.3 1.2Bilirubin (xULN) 0.8 0.6 2 0.8 0.7 1.1 0.6 0.7 0.8 0.9 0.8 0.9 0.8 0.8 0.6 0.4

20

SubjectID LabTest StudyDay xULNSubject 123456US ALT (SGPT) 0 0.8Subject 123456US ALT (SGPT) 8 0.6Subject 123456US ALT (SGPT) 14 6Subject 123456US ALT (SGPT) 18 3.3Subject 123456US ALT (SGPT) 29 3Subject 123456US ALT (SGPT) 33 5.2Subject 123456US ALT (SGPT) 36 2.5Subject 123456US ALT (SGPT) 40 1.9Subject 123456US ALT (SGPT) 44 1.8Subject 123456US ALT (SGPT) 48 2.8Subject 123456US ALT (SGPT) 52 1.2Subject 123456US ALT (SGPT) 54 1Subject 123456US ALT (SGPT) 56 1.2Subject 123456US ALT (SGPT) 59 0.8Subject 123456US ALT (SGPT) 64 1.5Subject 123456US ALT (SGPT) 70 1.4Subject 123456US AST (SGOT) 0 1Subject 123456US AST (SGOT) 8 0.9Subject 123456US AST (SGOT) 14 3.5

Study Day Treatment ALT (xULN) AST (xULN) Bilirubin (xULN)

0   0.8 1 0.88 X 0.6 0.9 0.6

14   6 3.5 218   3.3 2.8 0.829 X 3 1.4 0.733   5.2 2.5 1.136   2.5 1.8 0.640   1.9 1.6 0.744 X 1.8 1.6 0.848   2.8 1.8 0.952   1.2 1.2 0.854   1 1.3 0.956   1.2 1 0.859 X 0.8 1 0.864   1.5 1.3 0.670   1.4 1.2 0.4

  STUDY DAY  0 8 14 18 29 33 36 40 44 48 52 54 56 59 64 70Treatment   X     X       X         X    ALT (xULN) 0.8 0.6 6 3.3 3 5.2 2.5 1.9 1.8 2.8 1.2 1 1.2 0.8 1.5 1.4AST (xULN) 1 0.9 3.5 2.8 1.4 2.5 1.8 1.6 1.6 1.8 1.2 1.3 1 1 1.3 1.2Bilirubin (xULN) 0.8 0.6 2 0.8 0.7 1.1 0.6 0.7 0.8 0.9 0.8 0.9 0.8 0.8 0.6 0.4

21

What is the patient’s profile over time? ie, is it possible to display values for multiple lab parameters for subject(s) of interest?

22

What are the changes and percent changes from baseline over time? ie, are abnormal lab values a result of an abnormal baseline or have values changed on study?

23

What are the changes and percent changes from baseline over time? ie, are abnormal lab values a result of an abnormal baseline or have values changed on study?

24

[Courtesy - Andreas Brueckner – Bayer]

What is the patient’s profile over time? ie, is it possible to display values for multiple lab parameters for subject(s) of interest?

25

Are there multiple lab values that are elevated or abnormal, either concurrently or not? ie, how can we easily identify patients with simultaneous elevations in multiple lab tests over time?

26

What is the patient’s profile over time? What is the patient’s profile over time? How do we perform a comprehensive assessment of hepato-toxicity so that possible cases of drug induced liver injury are efficiently identified?

Labs and Liver Sub Team Members Robert Gordon (lead) – Johnson & Johnson Andreas Brueckner - Bayer Healthcare Susan Duke – GSK Qi Jiang - Amgen Mat Soukup – CDER

27

Former Sub Team Members Ted Guo– CDER Leslie Kenna – CDER Yaning Wang - CDER

Modern data graphics can do much more than simply substitute for small statistical tables. At their best, graphics are instruments for reasoning about quantitative information. Often the most effective way to describe, explore, and summarize a set of numbers – even a large set – is to look at pictures of those numbers. Furthermore, of all methods for analyzing and communicating statistical information, well-designed data graphics are usually the simplest and at the same time the most powerful.

The minimum we should hope for with any display technology is that it should do no harm.

There is no such thing as information overload, just bad design. If something is cluttered and/or confusing, fix your design

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

28

29

30

31

32

http://richworks.in/2010/04/50-most-stunning-examples-of-data-visualization-and-infographics/