Methods to Analyse The Economic Benefits of
a Pharmacogenetic (PGt) Test
to Predict Response to Biologic Therapy
in Rheumatoid Arthritis,
and to Prioritise Further Research
Alan Brennan1, Nick Bansback1,
1ScHARR, University of Sheffield, England.
Kip Martha2, Marissa Peacock2, Kenneth Huttner2
2Interleukin Genetics, Inc.
“Biologics”
Anakinra ($12,697), Etanercept ($18,850), Infliximab ($24,112)*
*Costs include monitoring
Anakinra 100mg
Etanercept 25mg eow
Infliximab 3mg/kg 8 weekly
“Biologics”
Anakinra ($12,697), Etanercept ($18,850), Infliximab ($24,112)*
Cytokines
Interleukin 1
*Costs include monitoring
Anakinra 100mg
Etanercept 25mg eow
Infliximab 3mg/kg 8 weekly
TNF alpha
TNF Alpha
“Biologics”
Anakinra ($12,697), Etanercept ($18,850), Infliximab ($24,112)*
Is Response Genetic?
91 patients, 150mg Anakinra, 24 week RCT1,2, gene = IL-1A +4845
Positive response = reduction of at least 50% in swollen joints
*Costs include monitoring
Anakinra 100mg
Etanercept 25mg eow
Infliximab 3mg/kg 8 weekly
1 Camp et al. American Human
Genetics Conf abstract 1088, 1999
2 Bresnihan
Arthritis & Rheumatism, 1998
“Biologics”
Anakinra ($12,697), Etanercept ($18,850), Infliximab ($24,112)*
Is Response Genetic?
24 week RCT1,2 , 91 patients, 150mg Anakinra,, gene = IL-1A +4845
Defined response = reduction of at least 50% in swollen joints
*Costs include monitoring
Anakinra 100mg
Etanercept 25mg eow
Infliximab 3mg/kg 8 weekly
1 Camp et al. American Human
Genetics Conf abstract 1088, 1999
2 Bresnihan
Arthritis & Rheumatism, 1998
“Biologics”
Anakinra ($12,697), Etanercept ($18,850), Infliximab ($24,112)*
Is Response Genetic?
*Costs include monitoring
Anakinra 100mg
Etanercept 25mg eow
Infliximab 3mg/kg 8 weekly
% achieving "Swollen50"
91 patients, 150mg Anakinra, 24 week RCT1,2, gene = IL-1A +4845
Positive response = reduction of at least 50% in swollen joints
100%
80%
60%
40%
20%
1 Camp et al. American Human
0%
Placebo Anakinra
100%
Gene
+ve
50%
Gene -ve
50%
Genetics Conf abstract 1088, 1999
2 Bresnihan
Arthritis & Rheumatism, 1998
Health Outcomes
• ACR20 response
-20% in swollen, and tender joints, and in 3 other measures
Health Outcomes
• ACR20 response
-20% in swollen, and tender joints, and in 3 other measures
ACR20 = 0.88 * Swollen50 score
(trial data)
Health Outcomes
• ACR20 response
-20% in swollen, and tender joints, and in 3 other measures
ACR20 = 0.88 * Swollen50 score
(trial data)
Response ==> symptom relief and delayed progression long term
Health Outcomes
• ACR20 response
-20% in swollen, and tender joints, and in 3 other measures
ACR20 = 0.88 * Swollen50 score
(trial data)
Response ==> symptom relief and delayed progression long term
• “Years in ACR20 Response” = primary outcome
3 Kobelt et al. Economic Conseque of Progression of RA in Swe. A&R 1999
Health Outcomes
• ACR20 response
-20% in swollen, and tender joints, and in 3 other measures
ACR20 = 0.88 * Swollen50 score
(trial data)
Response ==> symptom relief and delayed progression long term
• “Years in ACR20 Response” = primary outcome
• ACR 20 Response  0.8 reduction in HAQ (0 to 3 scale)
•
Utility
 0.86 - 0.2 * HAQ 3
3 Kobelt et al. Economic Conseque of Progression of RA in Swe. A&R 1999
ce
bo
An
ak
in
ra
G
en
e
+v
e
G
en
e
-v
Et
e
an
er
ce
pt
In
flix
im
ab
Pl
a
% achieving ACR20
Existing Uncertainty
100%
80%
60%
40%
20%
0%
50%
50%
2 Year Treatment Sequence Pathway
0 - 6 months
Respond?
Yes
6 - 12 months
AE or
lose efficacy?
No
12-18 months
Drug 1
…..
Yes
Drug 2
…..
Respond?
Yes
Drug 2
…..
No
Drug 3
…..
Drug 1
Drug 1
No
• Initial Response
Drug 2
Longer term discontinuation
A Pharmaco-Genetic Strategy
Before
0 - 6 months
Strategy 1
Gene +ve?
Yes
Respond ?
Yes
…..
No
…..
Respond?
Yes
…..
No
…..
Anakinra
PGt
No
Before
Strategy 2
Etanercept
0 - 6 months
Respond?
Yes
Anakinra
No
Strategy
Sequences
to Compare
A
PGt
E
I
-
Anakinra
Genetic
Etanercept
Infliximab
Maintenance
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
1st 2nd
PGt
A
E
I
E
A
I
A
E
I
I
E
PGt E
PGt
I
A
E
A
I
A
E
A
I
E
I
E
A
I
E
I
A
PGt E
-
3rd
I
E
A
I
A
E
I
-
4th
-
PGt sister
strategy
3
1
2
7
8
3
7
Trials
af
t
E er
af I
te
Ia rA
fte
r
Ia E
fte
A rA
af
te
A rE
af
te
rI
E
ak
G in
en ra
e
G +ve
en
Et e an v e
er
In cep
fli
xi t
m
ab
An
% achieving ACR20
Existing Uncertainty (2)
100%
80%
60%
40%
20%
0%
Sequence "priors"
Cost Assumptions
• Drugs and Monitoring
• Other Healthcare  HAQ
$Cost pa = $1,084 + $1,636 * HAQ 4
==> Responder
= $ 2,400 pa
Non Responder = $ 3,700 pa
• PGt = $200
• Excluding :Nursing Home Care, Employer Costs
• No uncertainty analysis
4 Yelin and Wanke . A&R 1999………...
2 Level EVSI - Research Design4, 5
4 Brennan et al Poster
SMDM 2002
5 Brennan et al Poster
SMDM 2002
2 Level EVSI - Research Design4, 5
0)Decision model, threshold, priors for uncertain parameters
4 Brennan et al Poster
SMDM 2002
5 Brennan et al Poster
SMDM 2002
2 Level EVSI - Research Design4, 5
0)Decision model, threshold, priors for uncertain parameters
1) Simulate data collection:
4 Brennan et al Poster
SMDM 2002
5 Brennan et al Poster
SMDM 2002
2 Level EVSI - Research Design4, 5
0)Decision model, threshold, priors for uncertain parameters
1) Simulate data collection:
• sample parameter(s) of interest once ~ prior
•
(1st level)
4 Brennan et al Poster
SMDM 2002
5 Brennan et al Poster
SMDM 2002
2 Level EVSI - Research Design4, 5
0)Decision model, threshold, priors for uncertain parameters
1) Simulate data collection:
• sample parameter(s) of interest once ~ prior
• decide on sample size (ni)
(1st level)
4 Brennan et al Poster
SMDM 2002
5 Brennan et al Poster
SMDM 2002
2 Level EVSI - Research Design4, 5
0)Decision model, threshold, priors for uncertain parameters
1) Simulate data collection:
• sample parameter(s) of interest once ~ prior
• decide on sample size (ni)
(1st level)
• sample a mean value for the simulated data | parameter of interest
4 Brennan et al Poster
SMDM 2002
5 Brennan et al Poster
SMDM 2002
2 Level EVSI - Research Design4, 5
0)Decision model, threshold, priors for uncertain parameters
1) Simulate data collection:
• sample parameter(s) of interest once ~ prior
• decide on sample size (ni)
(1st level)
• sample a mean value for the simulated data | parameter of interest
4 Brennan et al Poster
SMDM 2002
5 Brennan et al Poster
SMDM 2002
2 Level EVSI - Research Design4, 5
0)Decision model, threshold, priors for uncertain parameters
1) Simulate data collection:
• sample parameter(s) of interest once ~ prior
• decide on sample size (ni)
(1st level)
• sample a mean value for the simulated data | parameter of interest
2) combine prior + simulated data --> simulated posterior
4 Brennan et al Poster
SMDM 2002
5 Brennan et al Poster
SMDM 2002
2 Level EVSI - Research Design4, 5
0)Decision model, threshold, priors for uncertain parameters
1) Simulate data collection:
• sample parameter(s) of interest once ~ prior
• decide on sample size (ni)
(1st level)
• sample a mean value for the simulated data | parameter of interest
2) combine prior + simulated data --> simulated posterior
3) now simulate 1000 times
parameters of interest ~ simulated posterior
unknown parameters ~ prior uncertainty (2nd level)
4 Brennan et al Poster
SMDM 2002
5 Brennan et al Poster
SMDM 2002
2 Level EVSI - Research Design4, 5
0)Decision model, threshold, priors for uncertain parameters
1) Simulate data collection:
• sample parameter(s) of interest once ~ prior
• decide on sample size (ni)
(1st level)
• sample a mean value for the simulated data | parameter of interest
2) combine prior + simulated data --> simulated posterior
3) now simulate 1000 times
parameters of interest ~ simulated posterior
unknown parameters ~ prior uncertainty (2nd level)
4) calculate best strategy = highest mean net benefit
4 Brennan et al Poster
SMDM 2002
5 Brennan et al Poster
SMDM 2002
2 Level EVSI - Research Design4, 5
0)Decision model, threshold, priors for uncertain parameters
1) Simulate data collection:
• sample parameter(s) of interest once ~ prior
• decide on sample size (ni)
(1st level)
• sample a mean value for the simulated data | parameter of interest
2) combine prior + simulated data --> simulated posterior
3) now simulate 1000 times
parameters of interest ~ simulated posterior
unknown parameters ~ prior uncertainty (2nd level)
4) calculate best strategy = highest mean net benefit
5) Loop 1 to 4 say 1,000 times Calculate average net benefits
4 Brennan et al Poster
SMDM 2002
5 Brennan et al Poster
SMDM 2002
2 Level EVSI - Research Design4, 5
0)Decision model, threshold, priors for uncertain parameters
1) Simulate data collection:
• sample parameter(s) of interest once ~ prior
• decide on sample size (ni)
(1st level)
• sample a mean value for the simulated data | parameter of interest
2) combine prior + simulated data --> simulated posterior
3) now simulate 1000 times
parameters of interest ~ simulated posterior
unknown parameters ~ prior uncertainty (2nd level)
4) calculate best strategy = highest mean net benefit
5) Loop 1 to 4 say 1,000 times Calculate average net benefits
6) EVSI parameter set = (5) - (mean net benefit | current information)
4 Brennan et al Poster
SMDM 2002
5 Brennan et al Poster
SMDM 2002
2 Level EVSI - Research Design4, 5
0)Decision model, threshold, priors for uncertain parameters
1) Simulate data collection:
• sample parameter(s) of interest once ~ prior
• decide on sample size (ni)
(1st level)
• sample a mean value for the simulated data | parameter of interest
2) combine prior + simulated data --> simulated posterior
3) now simulate 1000 times
parameters of interest ~ simulated posterior
unknown parameters ~ prior uncertainty (2nd level)
4) calculate best strategy = highest mean net benefit
5) Loop 1 to 4 say 1,000 times Calculate average net benefits
6) EVSI parameter set = (5) - (mean net benefit | current information)



E X max E i NB(d,  ) |  i  max E NB(d,  )
d
d
4 Brennan et al Poster
SMDM 2002
5 Brennan et al Poster
SMDM 2002
Results - 6 months
4 strategies: A, E, I and PGt
Results - 6 months
4 strategies: A, E, I and PGt
Cost per Responder
$30,000
$25,000
$20,000
$15,000
$10,000
$5,000
$0
A
PGt
6 month Cost
% Responder
Cost per Resp
E
I
A
$6,349
43%
$14,764
PGt
$8,087
63%
$12,755
E
$9,425
71%
$13,275
I
$12,056
50%
$24,112
Results - 6 months
4 strategies: A, E, I and PGt
Incremental Cost per Responder Year
Gained
Cost per Responder
$30,000
$100,000
$25,000
$81,534
$80,000
$20,000
$60,000
6 month Cost
% Responder
Cost per Resp
E
I
A
$6,349
43%
$14,764
PGt
$8,087
63%
$12,755
E
$9,425
71%
$13,275
I
$12,056
50%
$24,112
A
Iv
v
E
PGt
E
A
PG
tv
$0
PGt DOM
PG
t
$0
Iv
$5,000
$17,608
$10,987
$8,521
PG
t
$20,000
v
$10,000
A
$40,000
A
$15,000
Base-case Results - 2 years
20 strategies: A, E, I and PGt sequences
Base-case Results - 2 years
20 strategies: A, E, I and PGt sequences
Optimal Strategy
Depends on Threshold:
$10k ==> maintenance therapy
$20k ==> sequence of 2 biologics
$25k ==> PGt + 2 biologics
$30k ==> PGt + 3 biologics
(20)
(11)
(9)
(19)
Base-case Results - 2 years
20 strategies: A, E, I and PGt sequences
Optimal Strategy
Depends on Threshold:
$10k ==> maintenance therapy
$20k ==> sequence of 2 biologics
$25k ==> PGt + 2 biologics
$30k ==> PGt + 3 biologics
Prob
Optimal
(20) 100%
(11) 42%
(9) 18%
(19) 43%
Incorporating Uncertainty
Overall EVPI
$million
$200
$178
$138
$150
$99
$100
$116
$50
$0
$0
$0
$0
$10k
$20k
$30k
$40k
Cost per Responder Year Threshold
• Assuming 25,000 per annum new patients
starting biologics over next 5 years
$50k
Partial EVPI: Key Uncertainties
PGt response
EVPI ($m)
$50
$40
$30
$20
$10
$0
$10
$15
$20
$25
$30
Threshold ($ 000)
$35
$40
$45
$50
Partial EVPI: Key Uncertainties
$50
E,I after any
biologic
EVPI ($m)
$40
$30
TNF after
Anakinra
$20
1st Line E,I,A
$10
TNF crossover
$0
$10 $15 $20 $25 $30 $35 $40 $45 $50
Threshold ($ 000)
Anakinra after
TNF
Partial EVSI: PGt Research only
Sample Size
Caveat: Small No.of Simulations on 1st Level
rf e
ct
Pe
50
00
20
00
10
00
50
0
20
0
10
0
50
20
$30.0
$25.0
$20.0
$15.0
$10.0
$5.0
$0.0
10
EVSI $m
EVSI for PGt Research only
(for threshold = $20,000 per responder year gained)
Interleukin Genetics Inc.
TARGET RA program
• Conceptual modelling identified key missing data and
helped prioritise further primary data collection
1. PGt test performance (increased sample size).
2. Etanercept / Infliximab performance in gene
subgroups
3. Anakinra response rate in anti-TNFα failures
Partial EVPI: TARGET RA Program
TARGET RA
$60
EVPI ($m)
$50
$40
$30
$20
$10
$0
$10
$15
$20
$25
$30
$35
Threshold ($ 000)
$40
$45
$50
Conclusions
• Early economic evaluation suggests potential for
a cost-effective pharmacogenetic test.
Conclusions
• Early economic evaluation suggests potential for
a cost-effective pharmacogenetic test.
• Expected value of information analysis has
quantified the key research priorities.
Conclusions
• Early economic evaluation suggests potential for
a cost-effective pharmacogenetic test.
• Expected value of information analysis has
quantified the key research priorities.
• EVSI can quantify the value of the specific
research design