Treatment For Life
Prophylaxis in Haemophilia A is more cost-effective
than on-demand therapy in a cost-utility model
Albert Farrugia 1,2,3 ,Josephine Cassar4,Mary Clare Kimber1,Megha Bansal1,Kathelijn Fischer5
Guenter Auserswald6,Brian O’Mahony7,Keith Tolley8,,Declan Noone7,Sonia Balboni1
1 Plasma Protein Therapeutics Association, Annapolis, Maryland, USA
2 School of Surgery, University of Western Australia, Crawley, Western Australia
3 School of Medicine, Australian National University, Canberra, Australia
4 Faculty of Health, University of Canberra, Canberra, Australia
5 Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands.
6 Ambulanz fuer Thrombose und Haemostasestoerungen Prof.- Hess Kinderklink, Klinikum Bremen-Mitte
7 Irish Haemophilia Society, Ireland
8 Tolley Health Economics Ltd, Derbyshire UK
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In praise of
“There are three criteria which must be fulfilled if a medicine should be reimbursed:
•
The human value principle; which underlines the respect for equality of all
human beings and the integrity of every individual.
•
The need and solidarity principle; which says that those in greatest need take
precedence when it comes to reimbursing pharmaceuticals. In other words,
people with more severe diseases are prioritised over people with less severe
conditions.
•
The cost-effectiveness principle; which states that the cost for using a medicine
should be reasonable from a medical, humanitarian and social-economic
perspective.”
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Swedish Pharmaceutical Benefits
Board 2007
Willingness to pay for prophylaxis
Cost Benefit study in Sweden
•
Contingent Valuation Method
–
Interview of 600 Swedish households to measure WTP
–
Question: Would you pay [x EUR] so that patients with severe hemophilia
can get Pro/OD treatment?
•
Results
–
Mean WTP
1. EUR 39 (OD) and EUR 65 (Pro) [p<0.01]
–
Cost/taxpayer
1. OD - EUR1.97 (95% CI 1.69–2.26)
2. PRO - EUR 5.56 (95% CI 4.94–6.17)]
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Carlsson et al. 2004 Haemophilia (2004), 10, 527–541
Cost Utility analyses (CUA) for Haemophilia
•
Most common form of health Study
technology assessment
•
Measures costs of Quality
Adjusted Life Years (QALYs)
•
Health payer agencies
worldwide have established
a threshold  $US50,000 for
Miners 2002 UK
₤46,500
₤30,000
Miners 2009 UK
₤37,000
₤30,000
Lippert 2005
Germany
Risebrough 2008
Canada
€1,200,000 Not applied
€2,200,000
CDN$542938 (escalated CDN$50,000 dose)
CDN$100,000
>CDN$1,000,000
the incremental cost of a
QALY above which they
ICER* for
Threshold ICER
prophylaxis vs on recommended by
demand
respective HTA
agency
(prophylaxis)
Colombo 2011
€40,250
€36,500 - €60,000
* Incremental Cost effectiveness ratio
would question costeffectiveness
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CUA and haemophilia
•
Several CUAs have been published for haemophilia prophylaxis vs
OD
•
Problematic features for rare, chronic disorders
–
Discounting of both costs and benefits decreases greatly the
effectiveness and increases the cost per QALY
–
Utility surveys with current instruments show that patients with
chronic disorders “underestimate” benefits, also resulting in
increased costs/QALY
–
Selective use of evidence, ignoring latest developments
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Effect of discounting
Benefits discounted at 1.5%
What does this mean?
•
If the benefit is
discounted by 1.5 %
instead of 3.5%
(NICE etc), the CE
Benefits discounted at 3.5%
increases to
“acceptable” levels
Assuming a WTP of ₤30,000/QALY
Miners Haemophilia (2009), 15, 881–887
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Utility measurements in CUAs for
prophylaxis vs on demand
Study
Instrument
Prophylaxis
On Demand
Miners
(2002,2009)
EQ-5D
1.05 – (0.006 x age)
0.84 – (0.006 x age)
Lippert (2005)
Short Form-6D
(HIV-ve)
<30 yo
>30 yo
0.76
0.70
0.75
0.66
Risebrough (2008)
Standard Gamble
0.95
With target joint 0.905
No target joint 0.875
Noone D (2011)
EQ-5D
0.88
0.72
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New CUA for hemophilia treatment
over whole of life
•
As the hemophilia population ages, new evidence indicates that
bleeding problems re-emerge
•
It is important to continue treatment over the whole of life
•
We have constructed a new CUA with the following key features
–
Pharmacokinetic dosage
–
Effect on inhibitors
–
Inclusion of soft tissue bleeds eg ICH etc
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Pharmacokinetic dosage
[FVIII] per week to maintain a trough level > 1% (IU/kg)
Daily
Alternate Day
Every Third
Day
1 – 6 10 – 65
years years
1–6
years
10 – 65
years
1–6
years
10 – 65
years
17
59
35
236
119
12
Collins et al 2010 JTH, 8: 269–275
0
1
2
3
4
5
6 days
Bjorkman and Berntorp Clin Pharmacokinet
2001; 40 (11): 815-832
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Cumulative incidence of inhibitor development :
prophylaxis versus on demand
The RODIN Study
Difference
only after 20
exposure
days
Gouw S C et al. Blood 2007;109:4648-4654
Gouw et al 2011 http://igiturarchive.library.uu.nl/dissertations/2011-1110200501/gouw.pdf
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Bremen Protocol – Prophylaxis for
tolerization
• FVIII started after obvious bleeding
tendency.
• Patients started at median age 10.7
months, median 1 Exposure Day on
demand (significantly earlier than
current primary prophylaxis regimens).
• Patients started once/week on 250 IU =
25–35 IU kg bw.
• This dose was maintained for as long
as possible.
• Frequency of treatment increased to
twice – three times weekly if necessary.
Patient
Outcomes
Standard
Prophylaxis
n=30
Early
Tolerization
N=40
Inhibitors (%)
14 (47)
1 (2.5)
High responders
8 (27)
0
Low responders
6 (20)
1 (2.5)
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Haemophilia (2010) 16, 256-262 & (2011), 1–2
Cost Utility analysis of prophylaxis vs OD therapy
over the whole of life
Willingness to Pay of $US50,000
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Key variables used to populate the
decision tree
Variable
Utility – on demand treatment , with and without inhibitors
Utility – prophylaxis treatment, with and without inhibitors
Incremental Cost Effectiveness threshold
Discount rate
Dosage – On Demand
Yearly Bleeding frequency – On Demand
Dosage – Prophylaxis
Yearly Bleeding Frequency – Prophylaxis (mean)
Dosage of FVIII – ICH – patients without inhibitors
Cost of FVIII concentrate per IU
Value
0.6705 – (0.0019*age)
0.9378 – (0.0026*age)
UK - £30,000
USA - $50 000
Sweden - NA
UK - 3.5% for costs, 1.5% for effectiveness (QALYs)
USA – 3.5% for costs and effectiveness
Sweden – 3% for costs and effectiveness
35 IU/kg
36
(1) Cycles 1 – 2 = 25IU/kg/week
(2) Cycles 3 – 20 = 59IU/kg/week
(3) Cycles 21 – 100 = 35 IU/kg/week
3
Day 1 – 111.7 IU/kg
Day > 2 – 50 IU/kg three times/week* 2.5 weeks
UK – 0.35£
USA - $1.00
Sweden – SEK 6.15
Mortality rates for patients
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Discounting – New NICE position
“Where the Appraisal Committee has considered it appropriate to
undertake sensitivity analysis on the effects of discounting because
treatment effects are both substantial in restoring health and
sustained over a very long period (normally at least 30 years), the
Committee should apply a rate of 1.5% for health effects and 3.5% for
costs.”
http://www.nice.org.uk/media/955/4F/Clarification_to_section_5.
6_of_the_Guide_to_Methods_of_Technology_Appraisals.pdf
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Outcomes of the cost-utility model
Payer Perspective
Cost
QALYs
Incremental
Cost
Incremental
QALYs
Cost/QALY
ICER
US
OD
Pro
$4,140,275
$4,563,274
19.42
25.48
$412,999
6.06
$213,759
$179,097
$68,109
OD
Pro
Sweden
£1,784,095
£1,503,229
27.16
36.85
- £280,866
9.69
£65,688
£40,798
Dominant
UK
OD
Pro
SEK
22,101,124
SEK
27,432,176
17.87
28.87
SEK
5,331,051
SEK 1,236,772
10.99
SEK 484,888
SEK 950,197
Sweden
(Daily Pro dosing)
OD
Pro
SEK
22,101,124
SEK
11,559,131
17.87
28.87
- SEK
10,541,993
SEK 1,236,772
10.99
SEK 400,386
Dominant
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Cost effectiveness acceptability curve
UK
USA
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The future
Higher dosages
Analysis of low frequency bleeding data:
the association of joint bleeds according to
baseline FVIII activity levels
Den Uijl et al Haemophilia Volume 17, Issue 1, pages 41-44
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The future
Longer acting products
Dumont J A et al. Blood 2012;119:3024-3030
Mei B et al. Blood 2010;116:270-279
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A new vision for evaluation
• Focusing on the patient’s problems
• Taking a patient’s perspective
• Accommodating of the patient’s preferences
• Allowing patient participation
• Building upon patient/physician partnerships
• Empowering the patient to improve their health
Source: Bridges, J and Jones C (2007) Patient based health technology assessment: A vision of what might one day be
possible, International Journal of Technology Assessment in Health Care. 23(1) pp30-35.
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The Patient –
Patient-centered outcomes research
DO NOT CONSIDER
COST-EFFECTIVENESS
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The patient or the community?
• “The principal objective of the National Health Service
ought to be to maximize the aggregate improvement
in the health status of the whole community.”
Anthony J. Culyer (1997)
• “The underlying premise of Cost Effectiveness
Analysis in health problems is that for any given level
of resources available, society (or the decision-making
jurisdiction involved) wishes to maximize the total
aggregate health benefit conferred.”
M.C. Weinstein and W.B. Stason (1977)
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In continued praise of
Sometimes the good effects of a medicine are so great that
they easily compensate for all costs. Then the treatment is
considered as cost saving. But we do not make such
high demands in order to consider if the use of a
medicine is cost-effective. That people get well,
do not experience pain and can live a more
normal life through using a medicine is important
enough for society to be willing to pay for it.
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Conclusions
•
Using emerging evidence on dosage and inhibitor incidence, and
factoring in discount rates reflective of chronic conditions,
prophylaxis is shown to be an acceptable option
•
More evidence regarding the key assumptions will contribute to the
model’s robustness
•
Emerging developments such as longer acting products and higher
dosage prophylactic regimens will influence the model
•
We encourage payers, policy makers, treaters and above all
patients to
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Accept nothing less than Treatment for All, and for Life
Harold Roberts in Freemantle
Australia October 1999
“and there shall be no more death,
neither sorrow, nor crying, neither shall
there be any more pain: for the former
things are passed away”
Revelations Ch21
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