Ins and outs of cost-effectiveness analysis
for treatments of rare diseases:
Fabry and Gaucher disease
Marcel G.W. Dijkgraaf, PhD
Clinical Research Unit
m.g.dijkgraaf@amc.nl
6th Health Policy Workshop
26 November 2014
My dear colleagues
Carla Hollak
Saskia Rombach
Laura van Dussen
Marieke Biegstraaten
Gabor Linthorst
2
…. between 14.30 and 15.30 hrs ….
TIPharma
3
4
Presentation lay-out
• Regulatory context of cost-effectiveness analyses
• Enzyme replacement therapies for Fabry & Gaucher
• Common grounds in analytic approach
• Distinct results
• Discussive remarks on CEAs of rare diseases
5
Why cost-effectiveness analyses of rare diseases?
Increasing numbers of orphan product designations 1983-2011 (FDA)
350
Number of Orphan Designations
300
250
200
150
100
50
0
83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11
6
Orphan drug designation
• Incentives:
– 10 year exclusivity after granting of
a marketing authorisation
– help with preparing the dossier to
meet regulatory requirements
– fee reductions, depending on size of
enterprise
– eligibility for EU-funded research
7
Orphan designation criteria
REGULATION (EC) No 141/2000 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL
of 16 December 1999
Less than 5 in 10,000 in the EU (around 250,000 people)
Life-threatening or chronically debilitating
Expected sales don’t cover the developmental costs: incentives needed
Likelihood of significant benefit over existing medicinal products or
methods
EMA/Committee on Orphan Medicinal Products assesses the available evidence
supporting that likelihood
8
Market authorisation
• significant benefit to be confirmed with data by
applicants at the time of market authorisation to maintain
orphan status
• significant benefit defined as ‘a clinically relevant
advantage or a major contribution to patient care’
• authorisation “under exceptional circumstances”,
following limited available evidence justified by
– Lack of trial data given rarity of the disease
– Lack of trial data given ethical issues
9
Why cost-effectiveness analyses of rare diseases?
If authorisation ‘under exceptional circumstances’, then
there will be a continuing need to assess the long term
effectiveness and cost-effectiveness of the orphan drug
under usual circumstances
10
Why cost-effectiveness analyses of rare diseases?
Increasing global orphan drugs demand by value in US$ million
2005
2006
2011
CAGR (%)
2006–2011
Biologics
30,200
35,300
53,400
9
Nonbiologics
24,300
23,400
28,400
4
Total
54,500
58,700
81,800
7
Sharma A, Jacob A, Tandon M, Kumar D. Orphan drug: Development trends and
strategies. Journal of Pharmacy and Bioallied Sciences 2010;2(4):290-299.
11
Presentation lay-out
• Regulatory context of cost-effectiveness analyses
• Enzyme replacement therapies for Fabry & Gaucher
• Common grounds in analytic approach
• Distinct results
• Discussive remarks on CEAs of rare diseases
12
Enzyme replacement therapies under evaluation
FABRY*
General name
GAUCHER
agalsidase alpha
agalsidase beta
Replagal
Fabrazyme
Cerezyme
VPRIV
Company
Shire
Genzyme
Genzyme
Shire
Authorisation
2001
2001
1991**
2010
Brand name
imiglucerase velaglucerase
*Specific requirement: outcomes research + pharmaco-economic evaluation
**Orphan Drug Legislation approved by European Parliament in 1999
Fabry disease
•
X-linked inherited deficiency of -Galactosidase A, an enzyme for
the breakdown of glycolipids (globotriasylceramide or GL-3) in
lysosomes
•
storage of glycolipids in vascular endothelial cells, smooth muscle
cells or other cell types
normal
deficiency
storage
increased
volume
Fabry disease symptoms & organ damage
•
•
•
•
•
•
•
•
•
Acroparesthesia / neuropathic pain in extremities, Fabry-crises
(periodic intense pain attacks)
fatigue
red-purple spots in the skin (angiokeratomas)
proteinuria
affected vision or hearing
gastrointestinal complaints
heart complaints & failure
renal complaints & failure
stroke / dementia
•
1 / 40,000
Clinical trials
agalsidase beta
agalsidase alfa
Eng et al NEJM 2001; 345: 9-16
Clearance of storage in renal capillaries
Baseline: Score = 3
Schiffmann et al JAMA. 2001;285:2743-2749
Decrease in painscore
Week 20: Score = 0
p = 0.021
7
6
5
4
3
2
1
0
0 m.
6 m.
Placebo
Agalsidase alfa
Type 1 Gaucher disease
•
deficiency of Glucocerebrosidase preventing the breakdown of
glucocerebrosides in lysosomes
•
storage primarily in spleen, liver & bone marrow cells
•
no involvement of central nervous system
Symptoms & organ failure:
• easy bleedings & bruises
• extreme fatigue
• anemia
• bone & joint crises (pain attacks)
• bone fracture
• large spleen and liver
•
1 / 70,000
Disease courses
Death
Severity ---------------------
Organ failure
Advanced disease
Early signs or
symptoms
No symptoms
Age ---------------------
Presentation lay-out
• Regulatory context of cost-effectiveness analyses
• Enzyme replacement therapies for Fabry & Gaucher
• Common grounds in analytical appproach
• Distinct results
• Discussive remarks on CEAs of rare diseases
19
Analytic approach to appraisal of ERTs
• Life-time Markov state-transition models
– Events occur repeatingly over time
– Longer term, lifetime consequences
• “Significant benefit”:
– Postponement of end-organ damage in years
– Quality adjusted life years
• Costs from a societal perspective
– Medical costs
– Costs of production loss
20
Simple Markov Model
Time
t
Well
Sick
Dead
t+1
Well
Sick
Dead
Fabry disease
22
Gaucher disease
23
untreated prior to ERT introduction
INTRO ERT
In absence of RCTs of sufficiently long duration...
treated after ERT introduction
Selection bias
untreated after ERT introduction
24
Assumptions
FABRY:
•
•
ERT only decreases the probability of progression to next state
no distinction between agalsidase alpha and aglasidase beta
because
– lack of evidence for superiority of either one
– comparable costs at the registered dose
GAUCHER:
•
ERT allows for recovery from signs/symptoms: otherwise, it only
decreases the probability of progression to next state
Both:
•
Health utilities, health care volumes and related costs (other than
ERT itself) for treated as well as untreated males and females are
similar for patients in the same disease state
25
Number of Fabry patients for data gathering
26
Data & estimates transition probabilities (TP)
•
Medical chart reviews prior to & after intro of ERT
•
Natural course:
– Kaplan-Meier survival curve analysis, with median (or less) durations in
years recalculated into TPs accounting for model cycle length; in case of
Gaucher accounting for competing risks
•
ERT:
– Multiple logistic regression on progression to next state for ERT duration in
years; odds ratio for treatment duration used together with median
treatment duration and model cycle length to calculate ‘1 minus relative
risk reduction’ as multiplicator of TPs natural course
•
Lower limit for probability of dying: general population CBS statistics
27
Fabry yearly transition probabilities
28
Data & estimates of health utilities
•
3-monthly EQ-5D questionnaires, after introduction of ERT
•
Five dimensions: mobility, self-care, daily activities, pain/complaints,
mood
•
Each dimension: no (1), some (2), severe problems (3)
•
Response patterns (e.g. 11231, or 21211) weighted with maximum
health utility of 1 in absence of any problems and with death taking
the value of 0. Weighting based on time trade-off based elicitation
techniques of preferences in general population
•
First averaging all measurements per patient per disease state, then
taking the average per disease state
29
Health utilities for Fabry disease states
30
Health utilities Fabry & Gaucher
Disease state
Fabry
Gaucher
Asymptomatic
0.87
0.93
Symptoms /
0.76
0.87
Recovery
Single complication
0.74
Splenectomy
0.75
Bone complication
0.86
Multiple complications
Malignancy
0.58
0.73
0.15
31
Data & estimates of costs
•
2004-2010 production data from national reference center; local unit
costing
•
3-monthly patient questionnaires for hospital care elsewhere, out-ofhospital care, and production loss
•
Unit costing compliant with national health care costing guideline
•
First averaging all measurements per patient per disease state per
year, then taking the average per disease state
•
Yearly drug costs:
– FABRY: prototypical yearly costs for a patient of 70kg
– GAUCHER: mean yearly costs per patient per disease state based on used vials of
400 IU per
32
Yearly costs of Gaucher disease
33
Presentation lay-out
• Regulatory context of cost-effectiveness analyses
• Enzyme replacement therapies for Fabry & Gaucher
• Common grounds in analytic approach
• Distinct results: the Fabry case
• Discussive remarks on CEAs of rare diseases
34
Cost-effectiveness analysis of ERT for Fabry
• Lifetime perspective with a 70-year time horizon
• Base case scenario:
– Males : females = 1 : 1; enter the model at birth; ERT prescribed
when symptoms developed; only medical costs included
• Six alternative scenarios:
– Delayed start with ERT: symptoms AND age>=40
– Lower health utility for untreated when in same state as treated
– For classical phenotypes only (no R112H or P60L substitutions
or intermediate level of lysoGb3)
– Natural course of disease adjusted for the use of ACE-inhibitors
or angiotensin blockers to prevent cardiovascular events
– No ERT in groups with multiple complications
– Including costs of production loss
35
CEA of ERT for Fabry: costs
36
CEA of ERT for Fabry: effects
37
CEA of ERT for Fabry: ICERs
38
Cost-effectiveness acceptability curve Fabry
39
CEA of ERT for Fabry: scenarios
40
CEA conclusions Fabry
• Small gains in effectiveness over a lifetime
• ERT has a low probability of being cost-effective
according to conventional standards
• High ICERs, hardly dependent on subgroup selection,
including production losses or early stopping if progress
• High ICERs, highly dependent on health utility contrast,
costs of ERT (sensitivity analysis), or comedication
41
Presentation lay-out
• Regulatory context of cost-effectiveness analyses
• Enzyme replacement therapies for Fabry & Gaucher
• Common grounds in analytic approach
• Distinct results: the Gaucher case
• Discussive remarks on CEAs of rare diseases
42
CEA of ERT for Gaucher
• Lifetime perspective with a 85-year time horizon
• Base case scenario:
– Enter the model at birth; ERT prescribed when symptoms
developed; only medical costs included
• Three alternative scenarios:
– Including costs of production loss (max 40 years)
– drop in ERT costs per vial (up to 25%)
– historical Dutch situation: distribution of patients across disease
states a time of market introduction (with or without asymtomatic
patients
43
The historical scenarios
44
CEA of ERT for Gaucher: ICERs (YFEOD)
45
CEA of ERT for Gaucher: ICERs (QALY)
46
Cost-effectiveness acceptability curve Gaucher
47
CEA conclusions Gaucher
• Substantial gains in effectiveness over a lifetime
• ERT has a low probability of being cost-effective
according to conventional standards
• ICERs hardly depend on including production losses and
highly depend on ERT costs
• Historical scenarios shows significance of early
treatment start
48
Presentation lay-out
• Regulatory context of cost-effectiveness analyses
• Enzyme replacement therapies for Fabry & Gaucher
• Common grounds in analytic approach
• Distinct results
• Discussive remarks on CEAs of rare diseases
49
Pro’s and con’s of CEAs
Why?
Why not?
• Money matters
• Rationing decision
making
• Reference case for
further optimizations
• Communicative vehicle
• Expensive D, cheap R
• Heavy assumptions &
high uncertainty level
• Lack of support
• Risk of anticipative
behavior
• Imbalanced focus across
settings within and
beyond health care
50
Thank you !