www.cytel.com ©2010 Cytel 1

`Exposure to Exposure

Any views or opinions presented in this presentation are solely those of the author and do not necessarily represent those of the company.

Gauri KhatuCytel Statistical Software & Services Pvt. Ltd.

www.cytel.cm 2

We will go through…

What is an Exposure dataset

Data Collection

Key variables in the Exposure analysis dataset

Derivations and Formulae

Tables and Listings

Challenges

www.cytel.com ©2012 Cytel 3

What is an Exposure dataset?

Details of subject’s exposure to protocol-specified study treatment

Crucial in making decisions about Safety and Efficacy

of study treatment

Useful to examine the subjects’ compliance rates

Required for regulatory submissions

www.cytel.com ©2012 Cytel 4

Data Collection

Actualdosing

Dose per Protocol

Dose regimen

Study medication date

Infusion time

Flag for dose change/ delay Reason for

change

www.cytel.com ©2012 Cytel 5

Data Collection

Methods:

Actual observations by the investigator

Automated dispensing devices

Subject Recall

Drug accountability

Protocol

www.cytel.com ©2012 Cytel 6

Case study

Pt ID 111

Trt Dose

D 20 mg/m2

Dosing on

Day 1, 8 and 15

Cycle duration

28 days

Example from Oncology

www.cytel.com ©2012 Cytel 7

Raw data…

PtID

Treatment Total daily dose (mg)

Planned dose

(mg/m2)

Was there a dose

change/ delay?

Reason for change of therapy

Reason for dose

change/ delay

Study medication

start

Study medication

end

111 D 36.4 20 0 21MAR2007 21MAR2007

111 D 36.4 20 0 28MAR2007 28MAR2007

111 D 36 20 0 04APR2007 04APR2007

111 D 0 20 1 Dose delay AE/ Lab Abn 18APR2007 18APR2007

111 D 0 20 1 Dose delay AE/ Lab Abn 25APR2007 25APR2007

111 D 36.2 20 0 02MAY2007 02MAY2007

111 D 36.2 20 0 09MAY2007 09MAY2007

111 D 36.2 20 0 16MAY2007 16MAY2007

111 D 36.2 20 0 30MAY2007 30MAY2007

111 D 35.8 20 0 06JUN2007 06JUN2007

www.cytel.com ©2012 Cytel 8

Key Variables in Exposure AD

Pt ID

Treatment Start

(Date)

Treatment End

(Date)

Cycle no.

CycleStart

(Date)

CycleEnd

(Date)

Planned Cycle

duration

Actual Cycle

duration

Missed doses?

Dosesreduction

Planned Dose

Planned DI

Actual DI

Relative DI

111

111

111

111

www.cytel.com ©2012 Cytel 9

Key Variables in Exposure AD

Pt ID

Treatment Start

(Date)

Treatment End

(Date)

Cycle no.

CycleStart

(Date)

CycleEnd

(Date)

Planned Cycle

duration

Actual Cycle

duration

Missed doses?

Dosesreduction

Planned Dose

Planned DI

Actual DI

Relative DI

From Raw

www.cytel.com ©2012 Cytel 10

Key Variables in Exposure AD

Pt ID

Treatment Start

(Date)

Treatment End

(Date)

Cycle no.

CycleStart

(Date)

CycleEnd

(Date)

Planned Cycle

duration

Actual Cycle

duration

Missed doses?

Dosesreduction

Planned Dose

Planned DI

Actual DI

Relative DI

Protocol specified

www.cytel.com ©2012 Cytel 11

Key Variables in Exposure AD

Pt ID

Treatment Start

(Date)

Treatment End

(Date)

Cycle no.

CycleStart

(Date)

CycleEnd

(Date)

Planned Cycle

duration

Actual Cycle

duration

Missed doses?

Dosesreduction

Planned Dose

Planned DI

Actual DI

Relative DI

www.cytel.com ©2012 Cytel 12

A look at some derivations…

Pt ID

Treatment Start

(Date)

Treatment End

(Date)

Cycle no.

CycleStart

(Date)

CycleEnd

(Date)

Planned Cycle

duration

Actual Cycle

duration

Missed doses?

Dosesreduction

Planned Dose

Planned DI

Actual DI

Relative DI

www.cytel.com ©2012 Cytel 13

Pt ID

Treatment Study Medication Start

Study Medication End

111 D 21MAR2007 21MAR2007

111 D 28MAR2007 28MAR2007

111 D 04APR2007 04APR2007

111 D 18APR2007 18APR2007

111 D 25APR2007 25APR2007

111 D 02MAY2007 02MAY2007

111 D 09MAY2007 09MAY2007

111 D 16MAY2007 16MAY2007

111 D 30MAY2007 30MAY2007

111 D 06JUN2007 06JUN2007

111 D 13JUN2007 13JUN2007

111 D 27JUN2007 27JUN2007

111 D 03JUL2007 03JUL2007

111 D 11JUL2007 11JUL2007

Treatment Start & End date

Pt ID Treatment Start

(Date)

Treatment End

(Date)

111 21-Mar-07 11-Jul-07

Duration of Exposure

www.cytel.com ©2012 Cytel 14

A course of treatment that is repeated on a regular schedule with periods of rest in between.

Dosing

Cycle 1 Cycle 2 Cycle 3 Cycle 4

Dosing Dosing Dosing

Cycle

www.cytel.com ©2012 Cytel 15

PtID

Total Daily Dose

(mg/m2)

Reason for change of

therapy

Reason for dose change/

delay

Study Medication

Date

111 36.4 21MAR2007

111 36.4 28MAR2007

111 36 04APR2007

111 0 Dose delay AE/ Lab Abn 18APR2007

111 0 Dose delay AE/ Lab Abn 25APR2007

111 36.2 02MAY2007

111 36.2 09MAY2007

111 36.2 16MAY2007

111 36.2 30MAY2007

111 35.8 06JUN2007

111 36 13JUN2007

111 36.2 27JUN2007

111 36.2 03JUL2007

111 36.2 11JUL2007

Cycle (Contd.)

Visit

C1 Day 1

C1 Day 8

C1 Day 15

C2 Day 1

C2 Day 8

C2 Day 15

C3 Day 1

C3 Day 8

C3 Day 15

C4 Day 1

C4 Day 8

C4 Day 15

Cycle No.

1

1

1

2

2

2

3

3

3

4

4

4

Cycle Start Date

21MAR2007

21MAR2007

21MAR2007

02MAY2007

02MAY2007

02MAY2007

30MAY2007

30MAY2007

30MAY2007

27JUN2007

27JUN2007

27JUN2007

Cycle End Date

?

www.cytel.com ©2012 Cytel 16

PtID

Total Daily Dose

(mg/m2)

Reason for change of

therapy

Study Medication

Date

111 36.4 21MAR2007

111 36.4 28MAR2007

111 36 04APR2007

111 0 Dose delay 18APR2007

111 0 Dose delay 25APR2007

111 36.2 02MAY2007

111 36.2 09MAY2007

111 36.2 16MAY2007

111 36.2 30MAY2007

111 35.8 06JUN2007

111 36 13JUN2007

111 36.2 27JUN2007

111 36.2 03JUL2007

111 36.2 11JUL2007

Cycle (Contd.)

Visit

C1 Day 1

C1 Day 8

C1 Day 15

C2 Day 1

C2 Day 8

C2 Day 15

C3 Day 1

C3 Day 8

C3 Day 15

C4 Day 1

C4 Day 8

C4 Day 15

Cycle No.

1

1

1

2

2

2

3

3

3

4

4

4

Cycle Start Date

21MAR2007

21MAR2007

21MAR2007

02MAY2007

02MAY2007

02MAY2007

30MAY2007

30MAY2007

30MAY2007

27JUN2007

27JUN2007

27JUN2007

As per Protocol Day prior to next cycle dosing

Previous cycle end 1 May 2007

www.cytel.com ©2012 Cytel 17

PtID

Total Daily Dose

(mg/m2)

Reason for change of

therapy

Study Medication

Date

111 36.4 21MAR2007

111 36.4 28MAR2007

111 36 04APR2007

111 0 Dose delay 18APR2007

111 0 Dose delay 25APR2007

111 36.2 02MAY2007

111 36.2 09MAY2007

111 36.2 16MAY2007

111 36.2 30MAY2007

111 35.8 06JUN2007

111 36 13JUN2007

111 36.2 27JUN2007

111 36.2 03JUL2007

111 36.2 11JUL2007

Cycle (Contd.)

Visit

C1 Day 1

C1 Day 8

C1 Day 15

C2 Day 1

C2 Day 8

C2 Day 15

C3 Day 1

C3 Day 8

C3 Day 15

C4 Day 1

C4 Day 8

C4 Day 15

Cycle No.

1

1

1

2

2

2

3

3

3

4

4

4

Cycle Start Date

21MAR2007

21MAR2007

21MAR2007

02MAY2007

02MAY2007

02MAY2007

30MAY2007

30MAY2007

30MAY2007

27JUN2007

27JUN2007

27JUN2007

Cycle End Date

01MAY2007

01MAY2007

01MAY2007

29MAY2007

29MAY2007

29MAY2007

26JUN2007

30MAY2007

30MAY2007

11JUL2007

11JUL2007

11JUL2007

1

1

21MAR2007

21MAR2007

01MAY2007

01MAY2007

www.cytel.com ©2012 Cytel 18

Cycle (Contd.)

PtID`

Total Daily Dose

(mg/m2)

Reason for change

of therapy

Reason for dose change/

delay

Study Medication

Date

Cycle No.

Cycle StartDate

Cycle EndDate

111 36.4 21MAR2007 1 21MAR2007 01MAY2007

111 36.4 28MAR2007 1 21MAR2007 01MAY2007

111 36 04APR2007 1 21MAR2007 01MAY2007

111 0 Dose delay AE/ Lab Abn 18APR2007 1 21MAR2007 01MAY2007

111 0 Dose delay AE/ Lab Abn 25APR2007 1 21MAR2007 01MAY2007

111 36.2 02MAY2007 2 02MAY2007 29MAY2007

111 36.2 09MAY2007 2 29MAY2007 29MAY2007

111 36.2 16MAY2007 2 02MAY2007 29MAY2007

111 36.2 30MAY2007 3 30MAY2007 26JUN2007

111 35.8 06JUN2007 3 30MAY2007 26JUN2007

111 36 13JUN2007 3 30MAY2007 26JUN2007

111 36.2 27JUN2007 4 27JUN2007 11JUL2007

111 36.2 03JUL2007 4 27JUN2007 11JUL2007

111 36.2 11JUL2007 4 27JUN2007 11JUL2007

Actual Cycle duration

42

28

28

15

www.cytel.com ©2012 Cytel 19

Key Variables in Exposure AD

Pt ID Treatment Start

(Date)

Treatment End

(Date)

Cycle no.

CycleStart

(Date)

CycleEnd

(Date)

Planned Cycle

duration

Actual Cycle

duration

Number of doses by cycle

Missed doses?

Doses reduction?

Planned Dose

Planned DI

Actual DI

RelativeDI

111 21-Mar-07 11-Jul-07 1 21-Mar-07 1-May-07 28 42 3 No No 20 3.9965 2.5905 0.6482

111 21-Mar-07 11-Jul-07 2 2-May-07 29-May-07 28 28 3 No No 20 3.9965 3.8786 0.9705

111 21-Mar-07 11-Jul-07 3 30-May-07 26-Jun-07 28 28 3 No No 20 3.9965 3.8571 0.9651

111 21-Mar-07 11-Jul-07 4 27-Jun-07 11-Jul-07 28 15 3 No No 20 3.9965 3.8786 0.9705

www.cytel.com ©2012 Cytel 20

Amount of treatment dose administered per unit time

PtID

Total daily dose

Cumulative dose

Actual cycle

duration

Actual DI

111 36.2

108 28 3.8571111 35.8

111 36

Cumulative Dose

DurationDose Intensity =

Dose Intensity

Planned DI

3.9965

www.cytel.com ©2012 Cytel 21

Fraction of the planned dose that a patient receives over a period of time

Pt ID

Cycle no.

Actual DI

Planned DI

Relative DI

111 1 2.5905 3.9965 0.6482

111 2 3.8786 3.9965 0.9705

111 3 3.8571 3.9965 0.9651

111 4 3.8786 3.9965 0.9705

Actual DIPlanned DI

RDI =

Relative Dose Intensity

www.cytel.com ©2012 Cytel 22

Fraction of the planned dose that a patient receives over a period of time

Pt ID

Cycle no.

Actual DI

Planned DI

Relative DI

111 1 2.5905 3.9965 0.6482

111 2 3.8786 3.9965 0.9705

111 3 3.8571 3.9965 0.9651

111 4 3.8786 3.9965 0.9705

Relative Dose Intensity

42 days!

www.cytel.com ©2012 Cytel 23

Key Variables in Exposure AD

Pt ID Treatment Start

(Date)

Treatment End

(Date)

Cycle no.

CycleStart (Date)

CycleEnd

(Date)

Planned Cycle

duration

Actual Cycle

duration

111 21-Mar-07 11-Jul-07 1 21-Mar-07 1-May-07 28 42

111 21-Mar-07 11-Jul-07 2 2-May-07 29-May-07 28 28

111 21-Mar-07 11-Jul-07 3 30-May-07 26-Jun-07 28 28

111 21-Mar-07 11-Jul-07 4 27-Jun-07 11-Jul-07 28 15

Row Number of doses by cycle

Missed doses?

Doses reduction?

Planned Dose

Planned DI

Actual DI

RelativeDI

1 (cont) 3 No No 20 3.9965 2.5905 0.6482

2 (cont) 3 No No 20 3.9965 3.8786 0.9705

3 (cont) 3 No No 20 3.9965 3.8571 0.9651

4 (cont) 3 No No 20 3.9965 3.8786 0.9705

www.cytel.com ©2012 Cytel 24

Tables and ListingsTable 1

Exposure to Treatment XYZ

Safety Population

1.5 mg/m2

3.0 mg/m2

6.1mg/m2

9.0 mg/m2

13.5mg/m2 Total

N=2 N=3 N=3 N=7 N=8 N=23

<1 1 (50.0%) 0 (0.0%) 0 (0.0%) 3 (42.9%) 4 (50.0%) 8 (34.8%)1 to less than 3 0 (0.0%) 2 (66.7%) 2 (66.7%) 3 (42.9%) 3 (37.5%) 10 (43.5%)3 to less than 6 0 (0.0%) 1 (33.3%) 0 (0.0%) 1 (14.3%) 1 (12.5%) 3 (13.0%)6 to less than 9 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%)9 to less than 12 1 (50.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 0 (0.0%) 1 (4.3%)12 or more 0 (0.0%) 0 (0.0%) 1 (33.3%) 0 (0.0%) 0 (0.0%) 1 (4.3%)

Mean 152 88.7 161.3 58.1 49.9 80.9S.D. 173.95 63.52 205.83 52.14 43.57 93.83Median 152 63 43 41 35.5 42Min,Max 29.0, 275.0 42.0, 161.0 42.0, 399.0 8.0, 161.0 8.0, 142.0 8.0, 399.0

Mean 98.7 99.4 97.6 88.4 79.9 89S.D. 2.45 1.08 1.04 16.64 14.91 14.49Median 98.7 99.8 97.6 96.7 85.7 96.5Min,Max 97.0, 100.5 98.2, 100.2 96.5, 98.6 53.4, 99.7 59.8, 96.4 53.4, 100.5

Relative dose intensity (%)

Number and % of patients with exposure (months)

Exposure (days)

www.cytel.com ©2012 Cytel 25

Dose (mg/m2) Cycle n

Relative DImedian, mean

0% of doses

>0%-<=25% of

doses>25%-<=50%

of doses>50% of doses

% of pts having dose reductions

20 All 31 94.5, 85.9 21 (67.7) 9 (29.0) 1 (3.2) 0 (0.0) 10 (32.3)1 31 95.9, 88.3 27 (87.1) 0 (0.0) 3 (9.7) 1 (3.2) 2 (6.5)2 26 93.4, 81.6 20 (76.9) 0 (0.0) 5 (19.2) 1 (3.8) 9 (34.6)3 13 91.8, 79.3 11 (84.6) 0 (0.0) 2 (15.4) 0 (0.0) 3 (23.1)4 7 50.7, 62.5 5 (71.4) 0 (0.0) 2 (28.6) 0 (0.0) 0 (0.0)5 4 56.6, 58.9 3 (75.0) 0 (0.0) 1 (25.0) 0 (0.0) 0 (0.0)6 4 70.5, 67.2 4 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (25.0)7 4 71.1, 71.2 4 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)8 4 71.8, 69.3 4 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)9 4 61.0, 63.7 4 (100.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)10 4 62.7, 62.9 3 (75.0) 0 (0.0) 1 (25.0) 0 (0.0) 0 (0.0)11 4 70.3, 64.5 3 (75.0) 0 (0.0) 1 (25.0) 0 (0.0) 1 (25.0)

% of Patients missing doses due to AE or lab abnorm.

Table 2

Dose intensity, missed doses, and dose reductions

Safety Population

Tables and Listings

www.cytel.com ©2012 Cytel 26

Listing 1Adverse events requiring dose adjustment or interruption by scheduleSafety PopulationDose 20 mg/m2

Tables and Listings

Countr/Center/Subject

Age/Sex/Race SAE

Adverse Event(REPORTED/ Preferred/ System organ class)

Start date/day

End date/day

Dur(day) Grade

Relat.to studymed.

Actiontaken

USA/999/000

81/M/Ca No INTERMITTENT HYPERGLYCEMIA/ Hyperglycaemia/ Metabolism and nutrition disorders

13MAR2007/7

16MAR2007/10

4 2 Not Susp

1

USA/999/111

69/M/Ca Yes ISCHEMIA ECG CHANGES/ Myocardial ischaemia/ Cardiac disorders

05APR2007/16

05APR2007/16

1 2 Susp 1

Action taken: 1=Study drug dosage adjusted/temporarily interrupted,

2=Study drug permanently discontinued due to this AE,

3=Concomitant medication taken,4=Non-drug therapy given,

5=Hospitalization/Prolonged hospitalization

www.cytel.com ©2012 Cytel 27

Clinical Significance

Increasing awareness about Dose Intensity

A way to examine compliance

Association with Survival

Vital factor in deciding Efficacy

Importance of Exposure

www.cytel.com ©2012 Cytel 28

Challenges

Study design

Cycle definition may not be standard

Dose interruptions and missed doses

Data issues and unclear specs

Sound programming skills

Validation

www.cytel.com ©2012 Cytel 29

Take away note…

ExposureOne of THE most crucial datasets

Associated with almost all other datasets

Be alert about the data, logic and program…

www.cytel.com ©2012 Cytel 30

www.cytel.com ©2012 Cytel 31

Email Address

Gauri Khatu–

gauri.khatu@cytel.com

THANK YOU