Transcript Document

Biological Differentiation
Part II
Dubai, United Arab Emirates
January 19th, 2009
Prof. Joachim R. Kalden
Director emeritus
Dept. of Internal Medicine III
Div. of Molecular Immunology
Nikolaus-Fiebiger-Center
University of Erlangen-Nuremberg
Overview
 Value for TNF antagonists in RA
 Economic evaluation for biologics in RA
 ENBREL & QoL of RA patients
 Measurement of RA impact
 Cost-effectiveness of ENBREL vs. biologics
 Impact of biologics on QALY
What is Value for a
Healthcare Intervention?
Value
 Does a healthcare intervention save lives or
reduce disease?
 Does the healthcare intervention save cost in a
health system?
 Does the healthcare intervention get people
back to normal living or work?
 Does the healthcare intervention do all the
above better than the existing therapies?
Value
Value = • [cost][benefit]
Cost
Benefit
 Acquisition
 Clinical
 Delivery
 Training
 Monitoring
 Cost to patient
 Travel
 Time off work
 Adverse events
 Healthcare professional visits
 State benefits
 Lost taxes
 Productivity loss
 Reduced number active joints
 Reduced damage
 Reduced mortality
 Reduced cardiovascular events
 Reduced osteoporosis
 Reduced fatigue
 Quality of life
 Reduced disability
 Reduced depression
 Improved work output
 Improved social life
 Intangible benefits
Need to Communicate with Payors
 Competitive world - we must be advocates for
our patients for healthcare resource!!
 “Key” areas - cardiology, oncology etc etc
 New expensive drugs hitting the market in “key”
areas
 Still major unmet need for rheumatology patients
 Make sure that rheumatology maintains its “share of
voice”
 Built on a principle of large amounts of good data in
many countries examining the impact of these agents
over the last 5 years
Treatment with TNF-blockers and
mortality risk in patients with
rheumatoid arthritis
Objective
 To assess mortality in patients with RA treated with TNF
inhibitors, compared to a standard RA population.
 921 RA patients started on TNF inhibitors in 1999 or
later recruited from regional register of RA patients to
cohort.
 Patient and disease characteristics including HAQ
scores gathered from regional register.
 Total cohort linked to national register for cause of
death.
 Overall mortality rates in those treated with TNF
inhibitors compared to those not treated with TNF
inhibitors estimated using standardised mortality ratios
(SMRs).
Results
SMR (or SMR ratio) at follow up (95% CI)
2 years
3 years
4 years
Anti-TNF exposed
All
1.2 (0.64-1.75)
1.20 (0.74-1.75)
1.50 (1.03-1.96)
(n = 921)
Men
1.65 (0.57-2.74)
1.79 (0.85-2.72)
1.86 (1.00-2.72)
Women
0.94 (0.33-1.55)
0.88 (0.38-1.37)
1.29 (0.75-1.83)
Non Anti-TNF exposed
All
1.51 (0.99-2.04)
1.54 (1.11-1.96)
1.50 (1.14-1.86)
(n = 652)
Men
1.18 (0.45-1.90)
1.24 (0.63-1.85)
1.19 (0.68-1.70
Women
1.74 (1.01-2.47)
1.73 (1.15-2.31)
1.70 (1.21-2.19)
SMR ratio
All
0.79 (0.42-1.44)
0.78 (0.47-1.27)
1.00 (0.66-1.49)
(anti-TNF exposed vs
exposed)
Men
1.41 (0.51-4.04)
1.44 (0.65-3.16)
1.56 (0.78-3.05)
Women
0.54 (0.22-1.22)
0.50 (0.24-0.99)
0.76 (0.44-1.28)
 Mortality ratios generated using Swedish national data as reference.
 TNF inhibitor treated patients appear to have reduced SMR compared to those
not treated with TNF inhibitors.
Conclusions
 Critical role for inflammation in RA associated
premature mortality
 Anti-TNF therapy may reduce mortality in RA
Reductions in Healthcare
Resource Use
Importance of Resource Use Reduction
Net Cost
Drug Costs
Post-treatment
Cost of Care
Pre-treatment
Cost of Care
Pre – Treatment
Total cost of Care
Cost
Offsets
Post – Treatment
Total cost of Care
 Traditional Model
(HTA): What does the
net cost of drug buy you
in health benefits?
 Emerging Model (Policy
Model): Can help shape
policy by alleviating
payors’ budgetary
concerns
Use of TNF therapy associated with a
decline in resource Use
Pre - Post Anti-TNF Treatment
60
56
50
40
30
28
22
20
20
10
8
10
0
Orthopaedic
Procedures
Major Joint
Replacement
Hand Surgery
Total Number of Days
Percent Per Patient Year
Pre - Post Anti-TNF Treatment
1000
857
800
593
600
400
332
113
200
0
Surgery-Related
Hospitalization
Non-Surgery
Hospitalization
 Subjects on etanercept or infliximab (Mar99 to Jun00)
 Four rheumatology centers in Helsingborg, Kristianstad, Trelleborg,
and Lund (n=116)
 Pre – Post comparison implemented at 12 months
Kobelt et al :Annals of the Rheumatic Diseases 2004;63:4-10
Biologics have a profound
effect on the quality of life of
patients with RA
ACR Responses (LOCF): TEMPO
MTX
E
MTX+E
ACR 20
ACR 50
ACR 70
100
85
86†
85†‡
% of Patients
80
69†‡
60
71†‡
67†‡
*
43†‡
49†‡
49†‡
40
20
0
12
*P<0.05,
24
36
E versus MTX
†P<0.05, combination versus MTX
‡P<0.05, combination versus E
12
24
36
12
24
36
months
TEMPO. Data on file. Wyeth.
HAQ Values (LOCF)
MTX
E
MTX+E
Mean Value
2
1.1
1
1.1
†‡
†‡
†‡
†‡
†‡
12
15
†‡
†
†‡
21
24
†
†
†
30
33
†‡
0.8
0
0
3
6
9
18
27
36
Months
† P<0.05, combination vs MTX
‡ P<0.05, combination vs E
TEMPO. Data on file. Wyeth.
Adalimumab (PREMIER):
52 and 104 weeks
ACR20
*
80 73
70
#
70
63
54
50
ACR70
80
*
69
60
% patients
ACR50
56
50
60
* *
59
62
50
80
Week 52
70
Week 104
60
46
42
43
37
50
40
40
30
30
30
20
20
20
10
10
10
0
0
0
ADA
+MTX
ADA
MTX
ADA
+MTX
ADA
*
* 47
46
40
MTX
*P<0.001 for adalimumab + MTX vs MTX alone and adalimumab alone
# P=0.043 for MTX vs adalimumab, others NS
26 28
ADA
+MTX
ADA
28 28
MTX
How Can We Measure the
impact of RA
at Home and Work?
Impact of RA on Work Disability?
 Work loss is common in RA
 Approximately 25% to 50% of patients with RA stop working within a
decade of disease onset
 Between 50% and 90% stop working before age 65
 Economic evaluation of impact on work
 Employment to unemployment
 Missed days of work (Absenteeism)
 Productivity loss (Presenteeism)
 Changing occupation
 Several factors contribute to work loss
 Biopsychosocial – support structure, type of job (white vs. blue collar;
management vs. clerical), education
 Economic incentive and disincentive to work
 Clinical factors: joint damage, pain, fatigue, sleep loss
 Missed days of work is important marker of future work loss
Work ability and disability in
rheumatology
 Patients with RA have reduced productivity,
increased lost work days and retire early
 Systematic review (Burton et al 2006): 66% of RA
patients experienced work loss in previous 12
months with median duration of 39 days
 Approximately one third of RA patients stop work
early
 Begins early after onset
 In FIN-RACo in first 5 yrs of disease (Puolakka et al,
ARD 2006):



75% lose work days
Mean productivity loss per year (human capital) €7217
Work loss related to HAQ and increasing erosions
Effect of TNF inhibitors
 RAPOLO results (Yelin et al A&R 2003)
 Compared cohort taking etanercept with control RA group
 Patients receiving etanercept worked on average 7.4 h more per
week
 Canadian study (Farahani et al, J Rheumatol, 2006)
 Compared cohort taking etanercept with control RA group
 In 1st 6m, lost work days significantly less in etanercept than
control group 2.5d v 7.8d (P=0.03). Difference not significant at
12 months
 Days with reduced productivity significantly less in etanercept
than control group at both 6 and 12 months (32.9 v 45.8; 60.7 v
86.5, both P=0.02)
Impact on Current Employment
Probability of Current Employment
Among Enbrel/non-Enbrel Users (%)
(n=497)
Diff = 16%
(95% CI 7-26%)
55
Unadjusted
71
Adjusted For
Demographics,
RA Status,
Occupation,
Industry
54
Diff = 20%
(95% CI 9-32%)
72
0
20
40
RAPOLO (n=238)
Yelin Ed et al. A&R 2003:48(11):3046-54
60
RA Panel (n=259)
80
Improvement in Presenteeism
Quantity of Current Employment (hours/week),
Among All Employed At Diagnosis
(n=497)
21.4
Unadjusted
26.8
Adjusted For
Demographics,
RA Status,
Occupation,
Industry
0
20.4
27.8
10
RAPOLO (n=238)
Yelin Ed et al. A&R 2003:48(11):3046-54
20
RA Panel (n=259)
30
Diff = 5.4
(95% CI 1.1, 9.7)
Diff = 7.4
(95% CI 2.6, 12.3)
Mean # of Times Missed Work for
Half a Day or More in Prior Month
Reduction in Absenteeism
Monotherapy
P<0.0001
2.4
2
P<0.0001
1.64
1.6
1.2
0.72
0.8
0.83
0.4
0
Baseline
(n=596)
6 months
(n=577)
12 months
(n=596)
Mean # of Times Missed Work for
Half a Day or More in Prior Month
Combination
P<0.0001
2.4
P<0.0001
 RADIUS 2: long-term US registry of
adults patients with RA who initiated
or added etanercept to their
treatment at enrollment
 Enrolled 5,000 patients from both
academic & community practices
 For patients who reported that they
were employed in some way at
baseline, the number of missed
workdays was analysed
2
1.6
1.43
1.2
0.66
0.8
0.83
0.4
0
Baseline
(n=895)
6 months
(n=875)
12 months
(n=596)
Gibofsky A et al. Curr Med Res Opin 2006;22:169-83.
% of Patients who had to take a less
physically demanding job
% of Patients who had to take a less
physically demanding job
Reduction in Need to Seek Less
Demanding Job
Montherapy
P<0.0001
P<0.0001
40
35
28.5
30
25
20
15
14.7
6 months
(n=446)
12 months
(n=463)
15
10
5
0
Baseline (n=463)
 For patients who reported
that they were employed
at baseline, the number of
missed workdays was
analysed
Combination
P<0.0001
P<0.0001
40
35
30
28.3
25
20
15
14.6
14.6
6 months
(n=666)
12 months
(n=685)
10
5
0
Baseline (n=685)
Gibofsky A et al. Curr Med Res Opin 2006;22:169-83.
Pharmacoeconomic
evaluations - why bother…?
Pharmacoeconomic evaluations - why
bother…?
 Resources are scarce
 People, time, facilities, equipment, knowledge
 Medications are expensive
 Over 20 therapies with cost > $4000 per year
 Assists in making the decision process explicit
 Can take into account preferences and attributes
How can we measure costeffectiveness of drugs?
Rheumatoid Arthritis
Health Economics Methodology
 Models based on DMARD and biologic sequences being
compared over a period beyond clinical trial timeframes
 Lifetime of disease model often taken to reflect chronicity
of disease, time of diagnosis, and age profile of patients
 Majority of models now have incremental cost per quality
adjusted life year as primary outcome measure
 Cost per QALY is derived from relationship between
change in HAQ and QoL from observational databases
 HTA bodies make economic analysis comparisons
based on analysis of data from key clinical trials
N.B. Data on “real world use” of TNFs not counted in costs in economic analysis
– no account of dose change taken into account
Quality Adjusted Life Years (QALY)
 QALY: composite measure of quality and quantity of life
 Health benefit of a healthcare intervention
 Reduced mortality, and/or
 Improved health
 QALY used because it allows comparisons across
diseases and interventions
 QALY support decision on healthcare resources
 Best use of limited resources:
 Fund interventions that offer more QALYs for marginal unit of
money spent
 Thresholds for cost-effectiveness


US: $50-100K for an incremental QALY
UK: £30k for an incremental QALY
Value Framework
An Illustration of QALYs
UTILITY
VALUE
1 QALY
1.0
Gain =1 QALY
Gains from QoL
Benefits
Gain= 1 QALY
0.5
Gains from Mortality
Benefits
1 QALY
YEARS
0
1
2
4
Independent Cost Effectiveness Review
Latest Results from NICE Appraisal – Nov 2006
TNF Cost Effectiveness calculated after 2 DMARD failures
in combination with MTX
Late RA data
Early RA data
HAQ
No HAQ
progression
HAQ
adalimumab
£64,000
£30,200
£30,200
etanercept
£49,800
£24,600
£28,500
infliximab
£139,000
£39,400
£30,400
No HAQ
>£20,000
What do you do when a
patient fails a TNF
Inhibitor?
Switching to a different TNF
antagonist or to any other
available biologic
Independent Cost Effectiveness Review
Latest Results from NICE Appraisal – Nov 2006
 ‘Speculative’ analysis carried out to explore possible bias from using
mix of RCT & observational data in the model
 Analysis based on data from RCTs of TNFα inhibitor monotherapy
in the cases of adalimumab and etanercept and combination
therapy in the case of infliximab
 In the analysis it was assumed that effectiveness was reduced by
30% to reflect the lesser effectiveness of a second TNFα inhibitor as
seen in the BSRBR
 Estimates of incremental cost effectiveness: ~ £30,000 per QALY
when etanercept used as a second TNFα inhibitor and ~£50,000 per
QALY when adalimumab and infliximab used as a second TNF α
inhibitor
Cost Effectiveness of Sequential
Use vs Standard DMARD Sequence
Sequence
ICER
(£/QALY)
ETN+MT X  IFX+MT X
£15,495
ETN+MT X  ADL+MT X
£22,749
IFX+MT X  ETN+M TX
£15,950
ADL+MT X  ETN+MT X
£24,455
MTX  ETN+MT X  IFX+M TX
£16,697
MTX  ETN+MT X  ADL+MT X
£17,409
MTX  IFX+MT X  ETN+M TX
£15,211
MTX  ADL+MT X  ETN+MT X
£19,158
Cost Effectiveness Analysis NICE 2006
Conclusion
 Independent UK HTA review has calculated
etanercept as the most cost effective TNF agent
 It is cost effective to prescribe an anti TNF after
another TNF has failed
 Etanercept has beneficial cost effectiveness
profile when used as a switch agent
 Etanercept also has beneficial cost effectiveness
profile vs Rituximab in TNF failure
 Ongoing studies will further elucidate the real life
costs of different biologics
Future developments
TNF blockers
1.
2.
3.
4.
Reduce time off work?
Improve quality of work?
Reduce other heath care costs?
Reduce mortality in women?
5. All of these?
In RA - it is cost effective to
1. Withhold TNF inhibitors totally and only use low cost
drugs?
2. Revert back to a DMARD after 1 TNF inhibitor
failure?
3. Swap TNF inhibitor if first agent fails?
4. Maintain patients on TNF inhibitors when no clinical
response?
5. Allow orthopaedic surgeons to fully manage
disease?
Summary
 Limited resources for healthcare
 Arthritis often seen as low priority
 Biologic therapies most effective in RA
 We must argue for our pts!
 TNF inhibitors cost effective




Early disease
More advanced disease
To swap after 1 TNF inhibitor failure
Cost-effectiveness measures further with experience
 Payors make the big choices - we must use the
increasing ammunition of evidence to support our
patients