optimal drug development programs and efficient licensing and reimbursement regimens neil hawkins...
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Optimal Drug Development Programs and Efficient Licensing and Reimbursement
Regimens
Neil HawkinsKarl Claxton
CENTRE FOR HEALTH ECONOMICS
Overview
• Societal and commercial value of Information• Decision rules incorporating value of information• Challenges
The Quantitative Estimate of the Value of Sample Information
The value of additional sample information is the value of the increased likelihood of selecting the optimum treatment arising from the reduction in uncertainty regarding treatment effects (and costs).
What is the optimum treatment?
The treatment with greatest expected net benefit in terms of costs and effects- Bayesian Decision Rule.
-20000 -10000 0 10000 20000
Net Benefit(tx) - Net Benefit(placebo)
Net Benefit(€)
Pro
ba
bili
tyFavours Placebo Favours Treatment
Decision Uncertainty
Expected Net Value of Sample Information (ENVSI)
Expectation over potential future samples of:
Net benefit from optimum decision made including the additional sample data —
Net benefit from optimum decision based on existing data—
Cost of collecting sample
Note: ENVSI < 0, if the optimum decision does not change due to extra sample data
Bayesian Simulation of Future Samples for Binomial Parameter
Sample P from current posterior distribution:
Pcurrent ~ beta(a,b)
Simulate Trial Data
rT ~ bin(n, PTx )
Calculate new posterior distribution
Pnew ~ beta(a+r,b+n-r)
Small Sample (n=1)
-20000 -10000 0 10000 20000
Net Benefit(tx) - Net Benefit(placebo)
Net Benefit(€)
Pro
ba
bili
ty
Favours Placebo Favours Treatment
Current SampleFuture Samples
Large Sample (n=2000)
-20000 -10000 0 10000 20000
Net Benefit(tx) - Net Benefit(placebo)
Net Benefit(€)
Pro
ba
bili
tyFavours Placebo Favours Treatment
Current SampleFuture Samples
Example Phase II Trial Results
Tx Placebo Response 16 8 Deaths 1 1 Total 49 45
χ2 Test: 2.0037, 1 df, p = 0.1569
Decision Analytic Model
Net Benefit =
P(Resp) x QALYs Gained | Resp x Monetary Value of a QALY - P(Death) x QALYs Lost | Death) x Monetary Value of a QALY -Treatment Cost
Example Parameter Estimates
QALYs Gained | Response : ~ N(0.7,0.12) x 4
QALYs Lost | Death : ~ N(0.7,0.12) x 4
Value of a QALY: £30,000
Treatment Cost Per Course :(<10% Response) £12,000 (≥10% & < 20% Response) £14,000
(≥20% Response) £16,000
Treatment Population: 20,000
Production Costs: £150,000,000
Trial Costs: (Fixed) £10,000,000 (per Patient) £20,000
Based on Current Data
• New treatment is cost-effective• New treatment would not get approval based on a
frequentist hypothesis test
Societal Value of Sample Information (Efficacy Trial)
0 100 200 300 400 500
05
00
01
00
00
15
00
02
00
00
25
00
0
Societal Value of Information Efficacy Endpoint
Sample Size
Va
lue
of I
nfo
rma
tion
Commercial Value of Sample Information
The value of increased sales due to the increased probability of regulatory and reimbursement approval arising from the extra information
ICH E9: Guidance on Statistical Principles for
Clinical Trials
Using the usual method for determining the appropriate sample size, the following items should be specified:
• probability of erroneously rejecting the null hypothesis • probability of erroneously failing to reject the null
hypothesis
ICH E1A: The Extent of Population Exposure to Assess Clinical Safety
• 100 patients exposed for a minimum of one-year is considered to be acceptable to include as part of the safety data base.
• It is anticipated that the total number of individuals treated with the investigational drug, including short-term exposure, will be about 1500.
Probability of Approval (Efficacy Endpoint – Current Regulatory Regimen)
0 100 200 300 400 500
0.0
0.2
0.4
0.6
0.8
Probability of Regulatory Approval Efficacy Endpoint
Sample Size
Pro
ba
bilit
y of
Ap
pro
val
Value of Sample Information (Efficacy Endpoint - Current Regulatory Regimen)
0 100 200 300 400 500
01
00
00
20
00
03
00
00
40
00
05
00
00
60
00
07
00
00
Societal and Commercial Value of Information Efficacy Endpoint
Sample Size
Va
lue
of I
nfo
rma
tion Commercial
Societal
What happens if we just use a Bayesian CE decision rule?
Value of Sample Information (Efficacy Endpoint - Bayesian CE Decision Rule)
0 100 200 300 400 500
01
00
00
20
00
03
00
00
40
00
05
00
00
60
00
07
00
00
Value of Information (Bayesian Decision Rule) Efficacy Endpoint
Sample Size
Va
lue
of I
nfo
rma
tion
CommercialSocietal
Societal Value of Sample Information (Utility Study)
0 20 40 60 80 100
02
00
40
06
00
80
01
00
0Societal Value of Information
Utility Endpoint
Sample Size
Va
lue
of I
nfo
rma
tion
Value of Sample Information (Utility Study – Current Regulatory Regimen)
0 20 40 60 80 100
02
00
00
40
00
06
00
00
80
00
0
Value of Information (Bayesian Decision Rule) Utility Endpoint
Sample Size
Va
lue
of I
nfo
rma
tion
CommercialSocietal
Implications
• Under current regulatory system we might expect a lack of outcomes and long-term data
• We need to consider uncertainty and resulting VOI when making decisions, not just expectations based on current data
• How should we do this?
Maybe we shouldn’t abandon frequentist hypothesis testing just yet?
The FDA view
“...A reasonable basis for a claim [of cost-effectiveness] depends on a number of factors relevant to the benefits and costs of substantiating a particular claim. These factors include: the type of product, the consequences of a false claim, the benefits of a truthful claim, the costs of developing substantiation for the claim ...”
Potential Industry Responses to Approval based on Value of Information
Reduce cost of uncertainty by research or price reduction
Trade-off between:
•Additional research-Cost, delay and uncertain outcome
-Entry and free rider
•Price reduction-Reduces EVI (for payoffs > 0) but reduces revenues
Approval Based on Expected Net Value of Sample Information
Approve new (more expensive?) treatment if expected net benefit of treatment is greater than existing treatment and expected net value of further sample Information is zero
Approval Based on Expected Net Value of Sample Information
• Hard to define set of endpoints, study designs and sample space over which we calculate value of sample information
• ENVSI is uncertain and will change as data become available. When is ENVSI defined?
• Many of the parameters required to estimate ENVSI are uncertain and may not be transparent
• Non-financial capacity restraints on further research• What decision do we make in the interim? - Sunk costs,
irreversibility and option value
Approval based on Expected Value of Perfect Information
Population EVPI for pricing decisions
£0
£500,000
£1,000,000
£1,500,000
£2,000,000
£2,500,000
£3,000,000
£3,500,000
£4,000,000
£4,500,000
£5,000,000
£0 £10,000 £20,000 £30,000 £40,000 £50,000 £60,000 £70,000 £80,000 £90,000 £100,000
Cost-effectiveness threshold
Po
pu
latio
n E
VP
I
Price = £24
Price = £12
Relative risk of progression for copaxone, Betaferon and rebif(22mg) (£14m, £13.6m and £7m respectively)
Also the cost of care, costs of relapse and quality of life (£10m, £7m and £6m respectively)
£86.2mRelapsing remitting and primary progressive multiple sclerosis (scenario 2)
Disease modifying therapies for multiple sclerosis
Specificity (£3.6m)£20mWomen aged 18 to 64 years (scenario 3)
Liquid Based Cytology
Relative risks of vascular and non vascular death
(£780m for ASA-MR-dipridamole compared to clopidogrel in the stroke subgroup)
£865m
£250m
£710m
£240m
Stroke
Transient Ischaemic Attack
Myocardial Infarction
Peripheral Arterial Disease
(scenario 2)
Clopidogrel and dipyridamole for secondary prevention
Quality of life with influenza, the effect of oselatimivir and amantadine (£44.3m, £0.43m and £0.23m respectively)
£66.7mOtherwise healthy adults not at elevated risk of complications
Neurominidase inhibitors
Relative risk of death for non acute PCI for GPA as medical management and for Clopidogrel(£85,041,000, and £68,137,000 respectively)
£171mAcute treatment following non-ST-elevation acute coronary syndrome (scenario 2)
Glycoprotein IIb/IIIa
Quality of life with and without PDT (£3,370,000 for 20/40)
£6.2m
£15.3m
Visual acuity 20/40
Visual acuity 20/80
AMD Screening
EVPI for parametersPopulation EVPIPatient GroupCase Study
Relative risk of progression for copaxone, Betaferon and rebif(22mg) (£14m, £13.6m and £7m respectively)
Also the cost of care, costs of relapse and quality of life (£10m, £7m and £6m respectively)
£86.2mRelapsing remitting and primary progressive multiple sclerosis (scenario 2)
Disease modifying therapies for multiple sclerosis
Specificity (£3.6m)£20mWomen aged 18 to 64 years (scenario 3)
Liquid Based Cytology
Relative risks of vascular and non vascular death
(£780m for ASA-MR-dipridamole compared to clopidogrel in the stroke subgroup)
£865m
£250m
£710m
£240m
Stroke
Transient Ischaemic Attack
Myocardial Infarction
Peripheral Arterial Disease
(scenario 2)
Clopidogrel and dipyridamole for secondary prevention
Quality of life with influenza, the effect of oselatimivir and amantadine (£44.3m, £0.43m and £0.23m respectively)
£66.7mOtherwise healthy adults not at elevated risk of complications
Neurominidase inhibitors
Relative risk of death for non acute PCI for GPA as medical management and for Clopidogrel(£85,041,000, and £68,137,000 respectively)
£171mAcute treatment following non-ST-elevation acute coronary syndrome (scenario 2)
Glycoprotein IIb/IIIa
Quality of life with and without PDT (£3,370,000 for 20/40)
£6.2m
£15.3m
Visual acuity 20/40
Visual acuity 20/80
AMD Screening
EVPI for parametersPopulation EVPIPatient GroupCase Study
Summary results of the NICE pilot study
Approval based on Expected Value of Perfect Information
Approve new therapy if Expected Value of Perfect Information is below a given threshold at an acceptable cost-effectiveness threshold
• Requires an arbritary EVPI threshold for approval• Parameters still uncertain. For example; relevant time
horizon, future technological change.
Approval based on Decision Uncertainty
Cost-effectiveness acceptability curves for pricing decisions
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
£0 £10,000 £20,000 £30,000 £40,000 £50,000 £60,000 £70,000 £80,000 £90,000 £100,000
Cost-effectiveness threshold
Pro
ba
bili
ty c
ost
-eff
ect
ive
Price = £24
Price = £12
Approval based on Decision Uncertainty
Approve new therapy if decision uncertainty is below a given threshold at an acceptable cost-effectiveness threshold
• Requires an arbritary uncertainty threshold for approval
Some Challenges
• How we consider uncertainty when decision making will influence the availability of evidence
• How do we frame explicit decision rules incorporating uncertainty?