Methods to Analyse The Economic Benefits of a Pharmacogenetic (PGt) Test
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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 Brennan 1 , Nick Bansback 1 , 1 ScHARR, University of Sheffield, England.

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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
“Biologics” Pharmacogenetic (PGt) Test

Anakinra ($12,697), Etanercept ($18,850), Infliximab ($24,112)*

*Costs include monitoring

Anakinra 100mg

Etanercept 25mg eow

Infliximab 3mg/kg 8 weekly


Biologics1
“Biologics” Pharmacogenetic (PGt) Test

Anakinra ($12,697), Etanercept ($18,850), Infliximab ($24,112)*

Cytokines

Interleukin 1 TNF alpha TNF Alpha

*Costs include monitoring

Anakinra 100mg

Etanercept 25mg eow

Infliximab 3mg/kg 8 weekly


Biologics2
“Biologics” Pharmacogenetic (PGt) Test

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

1 Camp et al. American Human

Genetics Conf abstract 1088, 1999

2 Bresnihan

Arthritis & Rheumatism, 1998

*Costs include monitoring

Anakinra 100mg

Etanercept 25mg eow

Infliximab 3mg/kg 8 weekly


Biologics3
“Biologics” Pharmacogenetic (PGt) Test

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

1 Camp et al. American Human

Genetics Conf abstract 1088, 1999

2 Bresnihan

Arthritis & Rheumatism, 1998

*Costs include monitoring

Anakinra 100mg

Etanercept 25mg eow

Infliximab 3mg/kg 8 weekly


Biologics4
“Biologics” Pharmacogenetic (PGt) Test

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

1 Camp et al. American Human

Genetics Conf abstract 1088, 1999

2 Bresnihan

Arthritis & Rheumatism, 1998

*Costs include monitoring

Anakinra 100mg

Etanercept 25mg eow

Infliximab 3mg/kg 8 weekly

100%

50%

50%


Health outcomes
Health Outcomes Pharmacogenetic (PGt) Test

  • ACR20 response

    -20% in swollen, and tender joints, and in 3 other measures


Health outcomes1
Health Outcomes Pharmacogenetic (PGt) Test

  • ACR20 response

    -20% in swollen, and tender joints, and in 3 other measures

    ACR20 = 0.88 * Swollen50 score (trial data)


Health outcomes2
Health Outcomes Pharmacogenetic (PGt) Test

  • 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 outcomes3
Health Outcomes Pharmacogenetic (PGt) Test

  • 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 outcomes4
Health Outcomes Pharmacogenetic (PGt) Test

  • 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


Existing uncertainty

50% Pharmacogenetic (PGt) Test

Existing Uncertainty

50%


2 year treatment sequence pathway
2 Year Treatment Sequence Pathway Pharmacogenetic (PGt) Test

  • Initial Response Longer term discontinuation


A pharmaco genetic strategy
A Pharmaco-Genetic Strategy Pharmacogenetic (PGt) Test

Strategy 1

Strategy 2


Strategy sequences to compare

1 Pharmacogenetic (PGt) Test

2

3

0

Strategy Sequences to Compare

A Anakinra

PGt Genetic

E Etanercept

I Infliximab

- Maintenance


Existing uncertainty 2
Existing Uncertainty (2) Pharmacogenetic (PGt) Test


Cost assumptions
Cost Assumptions Pharmacogenetic (PGt) Test

  • 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 design 4 5
2 Level EVSI - Research Design Pharmacogenetic (PGt) Test 4, 5

4 Brennan et al Poster

SMDM 2002

5 Brennan et al Poster

SMDM 2002


2 level evsi research design 4 51
2 Level EVSI - Research Design Pharmacogenetic (PGt) Test 4, 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 design 4 52
2 Level EVSI - Research Design Pharmacogenetic (PGt) Test 4, 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 design 4 53
2 Level EVSI - Research Design Pharmacogenetic (PGt) Test 4, 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 design 4 54
2 Level EVSI - Research Design Pharmacogenetic (PGt) Test 4, 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 design 4 55
2 Level EVSI - Research Design Pharmacogenetic (PGt) Test 4, 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 design 4 56
2 Level EVSI - Research Design Pharmacogenetic (PGt) Test 4, 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 design 4 57
2 Level EVSI - Research Design Pharmacogenetic (PGt) Test 4, 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 design 4 58
2 Level EVSI - Research Design Pharmacogenetic (PGt) Test 4, 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 simulate1000 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 design 4 59
2 Level EVSI - Research Design Pharmacogenetic (PGt) Test 4, 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 simulate1000 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 design 4 510
2 Level EVSI - Research Design Pharmacogenetic (PGt) Test 4, 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 simulate1000 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 design 4 511
2 Level EVSI - Research Design Pharmacogenetic (PGt) Test 4, 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 simulate1000 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 design 4 512
2 Level EVSI - Research Design Pharmacogenetic (PGt) Test 4, 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 simulate1000 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


Results 6 months
Results - 6 months Pharmacogenetic (PGt) Test

4 strategies: A, E, I and PGt


Results 6 months1
Results - 6 months Pharmacogenetic (PGt) Test

4 strategies: A, E, I and PGt


Results 6 months2
Results - 6 months Pharmacogenetic (PGt) Test

4 strategies: A, E, I and PGt


Base case results 2 years
Base-case Results - 2 years Pharmacogenetic (PGt) Test

20 strategies: A, E, I and PGt sequences


Base case results 2 years1
Base-case Results - 2 years Pharmacogenetic (PGt) Test

20 strategies: A, E, I and PGt sequences

Optimal Strategy

Depends on Threshold:

$10k ==> maintenance therapy (20)

$20k ==> sequence of 2 biologics (11)

$25k ==> PGt + 2 biologics (9)

$30k ==> PGt + 3 biologics (19)


Base case results 2 years2
Base-case Results - 2 years Pharmacogenetic (PGt) Test

20 strategies: A, E, I and PGt sequences

Optimal Strategy Prob

Depends on Threshold: Optimal

$10k ==> maintenance therapy (20) 100%

$20k ==> sequence of 2 biologics (11) 42%

$25k ==> PGt + 2 biologics (9) 18%

$30k ==> PGt + 3 biologics (19) 43%


Incorporating uncertainty
Incorporating Uncertainty Pharmacogenetic (PGt) Test

  • Assuming 25,000 per annum new patients starting biologics over next 5 years


Partial evpi key uncertainties
Partial EVPI: Key Uncertainties Pharmacogenetic (PGt) Test


Partial evpi key uncertainties1
Partial EVPI: Key Uncertainties Pharmacogenetic (PGt) Test


Partial evsi pgt research only
Partial EVSI: PGt Research only Pharmacogenetic (PGt) Test

Caveat: Small No.of Simulations on 1st Level


Interleukin genetics inc target ra program
Interleukin Genetics Inc. Pharmacogenetic (PGt) Test 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
Partial EVPI: TARGET RA Program Pharmacogenetic (PGt) Test


Conclusions
Conclusions Pharmacogenetic (PGt) Test

  • Early economic evaluation suggests potential for a cost-effective pharmacogenetic test.


Conclusions1
Conclusions Pharmacogenetic (PGt) Test

  • Early economic evaluation suggests potential for a cost-effective pharmacogenetic test.

  • Expected value of information analysis has quantified the key research priorities.


Conclusions2
Conclusions Pharmacogenetic (PGt) Test

  • 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


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