exposure to exposure - iasct to... · 2015-03-24 · ©2010 cytel 1 exposure to exposure` any views...
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`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.
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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
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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
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Data Collection
Actualdosing
Dose per Protocol
Dose regimen
Study medication date
Infusion time
Flag for dose change/ delay Reason for
change
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Data Collection
Methods:
Actual observations by the investigator
Automated dispensing devices
Subject Recall
Drug accountability
Protocol
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
?
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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
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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
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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
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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
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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
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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
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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!
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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
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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)
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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
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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
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Clinical Significance
Increasing awareness about Dose Intensity
A way to examine compliance
Association with Survival
Vital factor in deciding Efficacy
Importance of Exposure
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Challenges
Study design
Cycle definition may not be standard
Dose interruptions and missed doses
Data issues and unclear specs
Sound programming skills
Validation
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Take away note…
ExposureOne of THE most crucial datasets
Associated with almost all other datasets
Be alert about the data, logic and program…
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Email Address
Gauri Khatu–
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