non-compliance with drug dosing regimens: an underestimated bias in drug...
TRANSCRIPT
The experts on patient adherence
NON-COMPLIANCE WITH DRUG DOSING REGIMENS: AN UNDERESTIMATED BIAS IN DRUG TRIALS AND CLINICAL PRACTICE
Bernard Vrijens PhD, Chief Scientist Pharmionic Systems, Visé & University of Liège, Belgium
15 MARCH 2007 – BeAPP Brussels 2
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Need for a new discipline… Pharmionics
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15 MARCH 2007 – BeAPP Brussels 3
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Sources of Variances in Drug Response
Harter & Peck, Ann NY Acad Sci, 618: 563-571, 1991
manufacturing & distribution
prescribing
dispensing
Pharmionics
PK
PD drug response
15 MARCH 2007 – BeAPP Brussels 4
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Definitions
Vrijens & Urquhart, 2005 Journal of Antimicrobial Chemotherapy
Acc
epta
nce
EXECUTIONof the drug regimen
PERSISTENCE (days)
ADHERENCE/COMPLIANCE
Drugprescription
Endprescription
Dis
cont
inua
tionQUALITY OF
Need a simple but robust taxonomy
15 MARCH 2007 – BeAPP Brussels 5
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Reliable Assessment of Drug Exposure
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Vrijens & Urquhart, 2005 Journal of Antimicrobial Chemotherapy
15 MARCH 2007 – BeAPP Brussels 6
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Literature on Pill Counts
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15 MARCH 2007 – BeAPP Brussels 7
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Introducing Advanced Technology on Monitoring Adherence
Medication Event Monitoring System ®from AARDEX (Advanced Analytical Research on Drug Exposure)
15 MARCH 2007 – BeAPP Brussels 8
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A
Dosing Date (in Relative Dates)
Dos
ing
Tim
e (in
24
Hou
rs)
0 20 40 60 80
00
06
12
18
24
6 0123456 0123456 0123456 0123456 0123456 0123456 0123456 0123456 0123456 0
123456 0123456 012
Chronology plot
A “perfect” patient
0=Sunday;1=Monday; 2=Tuesday, …, 6=Saturday
15 MARCH 2007 – BeAPP Brussels 9
� Pharmionic
B
Dosing Date (in Relative Dates)
Dos
ing
Tim
e (in
24
Hou
rs)
0 20 40 60 80
00
06
12
18
24
123456 01
23456 0
12345
6 012345
6 0
123456
0
123456 0
12345
6 0
1234566 0
123456
0
123456 0
123456 0
12345
6
Chronology plot
A patient with delayed intake during the weekends
0=Sunday;1=Monday; 2=Tuesday, …, 6=Saturday
15 MARCH 2007 – BeAPP Brussels 10
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C
Dosing Date (in Relative Dates)
Dos
ing
Tim
e (in
24
Hou
rs)
0 20 40 60 80
00
06
12
18
24
0
45 1
2
3
4
5
6 0
3
4
5
3
64
0
2
5 4
6
1
1
4
4
5
0
1 3
45
0
2 1
Chronology plot
A « random » patient
0=Sunday;1=Monday; 2=Tuesday, …, 6=Saturday
Drug holiday
15 MARCH 2007 – BeAPP Brussels 11
� Pharmionic
Chronology plot
Dosing Date (in Relative Dates)
Dos
ing
Tim
e (in
24
Hou
rs)
0 20 40 60 80
00
06
12
18
24
601234
56012345601234560
123
4
56
0
1
23
4
5
6
012
345
601
23
0=Sunday;1=Monday; 2=Tuesday, …, 6=Saturday
A non persistent patient
15 MARCH 2007 – BeAPP Brussels 12
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Days
Per
cent
0 100 200 300
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Graphical display of the definitions
Persistence
Non acceptance
Non e
xecu
tion Adherence/compliance
Perfect adherence
Treatmentdiscontinuation
*# ���0�1�2.3...���� ����Source: AARDEX (Pharmionic database)
15 MARCH 2007 – BeAPP Brussels 13
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Time to dropout (Days)
Per
cent
age
of p
atie
nts
0 100 200 300
0.0
0.2
0.4
0.6
0.8
1.0
CENTRAL-NERVOUS SYSTEMDIABETESGASTRO-INTESTINAL DISEASEHIVHYPERTENSIONOSTEOPOROSIS
Data on Persistence
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Vrijens et al., Clinical Pharmacology and Therapeutics 2005
Overall, 40% of patients will have discontinued the prescribed drug after 12 months
15 MARCH 2007 – BeAPP Brussels 14
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Type of error
Time (days)
Frac
tion
of p
atie
nts
0 100 200 300
0.0
0.2
0.4
0.6
0.8
1.0
Details about quality of execution
Single day error in dosing regimen
�3 consecutive days with errors in dosing regimen
2 consecutive days with errors in dosing regimen
Non execution by type of dosing errors
Source: AARDEX (Pharmionic database)
15 MARCH 2007 – BeAPP Brussels 15
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Cumulative proportion of pts affected by poor execution
Time (days)
Per
cent
age
of p
atie
nts
0 100 200 300
020
4060
8010
0
1234
…
12
One day without dosing
Source: AARDEX (Pharmionic database)
15 MARCH 2007 – BeAPP Brussels 16
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Cumulative proportion of pts affected by poor execution
Time (days)
Per
cent
age
of p
atie
nts
0 100 200 300
010
2030
4050
60
1
2
3
4
…
12
Drug holiday (3 consecutive days without dosing)
Source: AARDEX (Pharmionic database)
15 MARCH 2007 – BeAPP Brussels 17
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Weekend Effect
61
70.5
87.1
97.195.695.9
60.6
37.2
54.4
67.166.671.9
78.9
20
40
60
80
100
Probability of drug intake in the morning Probability of drug intake in the evening
Pro
b abi
lity
Baseline
Source: AARDEX (Pharmionic database)
Mon Tue Wed Thu Fri Sat Sun
15 MARCH 2007 – BeAPP Brussels 18
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Patient id = 716 Treatment 400/300
Dosing Date
Dos
ing
Tim
e
0 100 200 300
2
2
3
3
4
4
56
012
2
3
3
4
4
5
5
6
0
0
1
1
2
2
3
3
4
4
5
5
6
6
0
0
1
1
2
2
3
3
4
4
5
5
6
6
0
0
1
1
2
2
3
3
4
4
56
0
0
1
1
2
2
3
3
4
4
56
6
0
0
1
1
2
2
3
3
4
4
5
5
6
0
1
1
2
2
34
4
5
5
6 0
0
1
2
2
3
3
4
4
5
5
6
6
0
0
1
1
2
2
3
3
4
4
51
1
2
2
3
3
4
4
5
5
6
6
0
12
2
3
3
4
4
5
6
6
0
1
1
2
2
3
3
4
4
5
5
6
6
0
0
1
2
2
3
3
4
4
5
6
01
23
3
4
4
5
5
6
0
0
1
2
2
3
4
4
5
5
6
6
0
0
1
1
2
2
3
3
4
4
56
6
0
0
12
2
34
4
5
56
1
2
2
46
6
0
0
1
1
234
4
5
5
6
0
1
1
23
3
456 0
0
1
1
2
2
3
3
456
6
0
1
1
23
3
456
1
23
3
4
4
562
2
4
4
5
5
6
6 0
1
1
2
2
34
4
56
6
0
0
1
1
2
4
5
0
6
2
2
3
3
456
0
23
3
45613
3
4
4
5
0
1
1
23
3
4
4
56
2
34
0
112
2
4 5
5
6
01
1
23
4
562
2
34
4
5
3
3
4
4
6
0
3456245
0
34563452456
23
3
6 0
1
2341456123
3
45 3
3
4
51
1
2
2
3
4
4
61
1
234561
VV VVV VVVV VVVVVVVVVVVVV VVVVVVVVVVVV VVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVV
03:00
06:00
09:00
12:00
15:00
18:00
21:00
24:00
03:00
1 PK4 12 24 48
START END
03:00
06:00
09:00
12:00
15:00
18:00
21:00
24:00
03:00
2
3
4
5
Log1
0 V
iral L
oad
Deteriorating adherence – lose viral control
0=Sunday;1=Monday; 2=Tuesday, …, 6=SaturdayHIV
15 MARCH 2007 – BeAPP Brussels 19
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The better the execution, the longer the persistence
Time (days)
Pro
porti
on o
f pat
ient
s
0 100 200 300
0.0
0.2
0.4
0.6
0.8
1.0
>90%
]80-90]%
]60-70]%
]50-60]%
<=50%
]70-80]%
PKC in HIV, N=1311pts
15 MARCH 2007 – BeAPP Brussels 20
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Multi-steps Successful Intervention
Acc
epta
nce
EXECUTIONof the drug regimen
Dis
cont
inua
tion
MOTIVATIONS- physician/nurse- pharmacist- disease understanding- targeted intervention- word of mouth- (DTC promotion)
BARRIERS- negative TV/print- word of mouth- disinterest
Patient
History
-Other therapies- Family history- Way of life- Relation with health care system
EFFECT
Vrijens, et al., Pharmacoepidemiology and Drug Safety, 2006
15 MARCH 2007 – BeAPP Brussels 21
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What can be measured, can be managed
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Measurement Guided Medication Management (MGMM)
REALISTIC & ACCURATE measurement of day by day execution
of the dosing regimen
Deming WE
15 MARCH 2007 – BeAPP Brussels 22
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Individual example of successful MGMM
Identification of adherence problems and result of intervention
3456012456012345
5
6012345601234456
012345601234560123456012
34560123455601
234560123445
60123456
0123455
601234560123456012345
5
60123456612345601
25
VVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVVV
Days on treatment
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Dos
ing
Tim
e
0 100 200 300
00:00
06:00
12:00
18:00
24:00
23
60
4
5 56
2 1 1
1
10
1234
4 45
60
3
12345601234560
345
6012345
60123456012
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23
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012345601
2345601234560
1
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012345601
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VVVVVVVVVVVVVVV VV V V
2 3 4 5 6 7
15 MARCH 2007 – BeAPP Brussels 23
� Pharmionic
Individual example of successful MGMM
Dosing Date
Dos
ing
Tim
e
0 100 200 300 400
VVVVVVVVVVVVVVVVVVVVVVVVV VVVVVVVVVVVVVVVV V VVV VVVVVVV VVVVVVVVVVVV VVV VVVV VVVV
03:00
06:00
09:00
12:00
15:00
18:00
21:00
24:00
03:00
ENDSTART
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Identification of adherence problems and result of intervention
15 MARCH 2007 – BeAPP Brussels 24
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15 MARCH 2007 – BeAPP Brussels 25
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RE+
RE+
RE-
RE-
Regions selected based on good collaboration between pharmacists and GP
MGMM tested in Lipid Lowering
Vrijens et al, Pharmacoepidemiology and Drug Safety, 2006
15 MARCH 2007 – BeAPP Brussels 26
� Pharmionic
MGMM tested in Lipid Lowering
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# pharmacies / # subjectsVrijens et al, Pharmacoepidemiology and Drug Safety, 2006
15 MARCH 2007 – BeAPP Brussels 27
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MGMM tested in Lipid Lowering
~86%
~71%
Vrijens, et al., Pharmacoepidemiology and Drug Safety, 2006
P<0.01
Daily Percentage of adherers
Days since inclusion
%
0 50 100 150 200 250 300
6070
8090
100
InterventionNo Intervention
Differenceof 15%
15 MARCH 2007 – BeAPP Brussels 28
� Pharmionic
Time to dropout (Days)
Per
cent
age
of p
atie
nts
0 50 100 150 200 250 300
0.6
0.7
0.8
0.9
1.0
No InterventionIntervention
Persistence at300 days
87%
74%
P=0.002 (M-H)
Frac
tion
ofpa
tient
s
Non acceptance: 10 patients
Persistence=time to treatment discontinuation
MGMM tested in Lipid Lowering
InterventionNo Intervention
Vrijens, et al., Pharmacoepidemiology and Drug Safety, 2006
15 MARCH 2007 – BeAPP Brussels 29
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Dosing Day (Relative to Visit 1)
Per
cent
of P
atie
nt W
ith In
take
-30 -20 -10 0 10 20 30
8085
9095
100
ReinforcedNo InterventionIntervention
No Intervention
30 DAYS BEFORE INTERVENTION 30 DAYS AFTER INTERVENTION
MGMM tested in Lipid Lowering
Execution = daily % of patients with drug intake among those who persist
P < 0.001
15 MARCH 2007 – BeAPP Brussels 30
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Conclusion from MGMM case studies
� &�&&���� ��� ������������������ ����� ������ ��� ���3����� ������������%��� �������E����� B�������������������� �������� �������3������� ���3��J���� ������������ ������������3��� �6 � � ����� ��� ���3�K
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� &�&&� ��%��� 6��� ���� ���� � �������� ��
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No 2 drugs will require the same solution!
Importance of using the right interventional tools
15 MARCH 2007 – BeAPP Brussels 31
� Pharmionic
Dosing Date
Dos
ing
Tim
e
0 20 40 60 80 100 120
03:00
06:00
12:00
18:00
24:00
03:00
Start V1 V2 V3 End fdur
Comp
V
Pers.
Dosing Date
Dos
ing
Tim
e
0 20 40 60 80 100 120
03:00
06:00
12:00
18:00
24:00
03:00
Start V1 V2 V3 End fdur
Comp
V V V V
Pers.
ALL of those 4 patients are 79% « compliant »!
Dosing Date
Dos
ing
Tim
e
0 20 40 60 80 100 120
03:00
06:00
12:00
18:00
24:00
03:00
Start V1 V2 V3 End fdur
Comp
V VVVVVVVVV
Pers.
Dosing Date
Dos
ing
Tim
e
0 20 40 60 80 100 120
03:00
06:00
12:00
18:00
24:00
03:00
Start V1 V2 V3 End fdur
Comp
V VVVVVVVVVVVVVVVVVVVVVVVV
Non Pers. Color code
2 doses1 doses0 doses
>2 doses
15 MARCH 2007 – BeAPP Brussels 32
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Patient management model
15 MARCH 2007 – BeAPP Brussels 33
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Breaking The Downward Spiral
15 MARCH 2007 – BeAPP Brussels 34
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kr kd(t)Nt
kd (t) is the time-dependent discontinuation ratekr is the recruitment rate of naive patientsk’r is the re-recruitment rate of non-naive patientsk’m (t) is the time-dependent mortality of formerly treated patientskm (t) is the time-dependent mortality of treated patients
At Rt
k’r
k’m(t)
km (t)
Demokinetic model
Naive Treated Pts who stopped
Rate of drug consumption at time t is : At x Regimen x Compliance
15 MARCH 2007 – BeAPP Brussels 35
� Pharmionic
Time in Months
Num
ber o
f pat
ient
s ( u
nit =
100
000)
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 years follow-up with 10,000 patients recruited/mo.
Perfect persistence
Observedpersistence
Time in Months
Num
ber o
f pat
ient
s ( u
nit =
100
000)
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Time in Months
Num
ber o
f pat
ient
s ( u
nit =
100
000)
0 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
It is the single largest untapped value opportunity in the industry!
Recouping The Hidden Blockbuster
10K/mo
20K/moRecruit more
subjects
t1/2= 1yr
t1/2=10yr
Increasepersistence
40% increasein total exposure
15 MARCH 2007 – BeAPP Brussels 36
� Pharmionic
Thank you for your attention
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