CHE Economic evaluation seminar 12th April 2016. Dr Martin Henriksson, Division of Health Care Analysis, Department of Medical and Health Sciences, Linköping University, Sweden

1. ECONOMIC EVALUATON OF NON-INVASIVE
INVESTIGATION OF STATIC AND DYNAMIC LIVER
FUNCTION TO ASSIST CLINICAL DECISION MAKING
IN HEPATOCELLULAR CARCINOMA
Martin Henriksson
Division of Health Care Analysis, Department of Medical and
Health Sciences, Linköping University, Sweden

2. Outline
2
• Background
• Economic evaluation
• Discussion

3. Background
3

4. Liver Function Evaluation

5. 5
Healthy liver Not so healthy liver
Fibrosis/cirrhosis
Hepatocellular carcinoma (HCC)

6. Primary liver cancer (HCC)
6
• Most common type of liver cancer
• Most cases are secondary to either a viral hepatitis infection (hepatitis
B or C) or cirrhosis (alcoholism being the most common cause)
• Treatments include:
– Surgical resection
• Remove the tumor together with surrounding liver tissue while preserving
enough liver remnant for normal body function
– Transplant
– Radiofrequency ablation
• Imaging guidance to place a needle electrode into a liver tumor. High-frequency
electrical currents are passed through the electrode, creating heat that destroys
the cancer cells
– Trans catheter chemoembolization (TACE)
• Delivering cancer treatment directly to a tumor through minimally-invasive
means

7. 7
Decision to perform surgery based on liver function and other
parameters
Fibrosis/cirrhosis
Hepatocellular carcinoma (HCC)
In general there is limited information:
• Liver function (a series of lab values)
• ECOG (performance status)
• Tumor burden (Staging)
• Age

8. 8
How surgery is performed is also based on knowledge of liver function
The amount that can be resected
depends on global and local liver
function:
Limited knowledge less precision in
surgery

9. 9
How surgery is performed is also based on knowledge of liver function
The amount that can be resected
depends on global and local liver
function:
Limited knowledge less precision in
surgery
Better knowledge better precision in
surgery

10. 10
How surgery is performed is also based on knowledge of liver function
The amount that can be resected
depends on global and local liver
function:
Limited knowledge less precision in
surgery
Better knowledge better precision in
surgery

11. 29 FEBRUARY 2016 11CMIV flagship project
The vision with the current research programme is to
develop a comprehensive and non-invasive diagnostic MR-
toolkit for investigating liver diseases
Inflammation Steatosis
Fibrosis
and cirrhosis
Iron loading
Liver disease
e.g. NAFLD, NASH, PSC
Liver
function

12. 1229 FEBRUARY 2016CMIV flagship project
Inflammation Steatosis
Fibrosis
and cirrhosis
Iron loading
Liver disease
e.g. NAFLD, NASH, PSC
Liver
function
Multimodal MR
• Fat content
• Fat and muscle content and distribution
• Fibrosis stage
• Iron loading
• Liver function
• Energy levels, phosphorus metabolism
• Liver blood flow
• Inflammation grade
• Conventional images for morphological investigation
Diagnosis &
treatment
Blood panels

13. Our Group and Researchers Involved with our Projects
13
MR Physics and Systems Biology
• Professor Peter Lundberg (PhD)
• Lektor Olof Dahlqvist Leinhard (PhD)
• Lektor Gunnar Cedersund (PhD)
• Lektor Petter Dyverfeldt (PhD)
• Mikael Forsgren (PhD student)
• Markus Karlsson (PhD student)
• Thobias Romu (PhD student)
Hepatology
• Professor Stergios Kechagias (MD, PhD)
• Docent Mattias Ekstedt (MD, PhD)
• Patrik Nasr (MD, PhD student)
Liver Surgery
• Professor Per Sandström (MD, PhD)
• Anna Lindhoff-Larsson (RN, PhD student)
Radiology
• Lektor Nils Dahlström (MD, PhD)
• Bengt Norén (MD, PhD)
• Amir Razavi (MD, PhD)
• Professor Örjan Smedby (MD, PhD; KTH)
• Docent Torkel Brismar (MD, PhD; KS)
Pathology
• Professor Darren Treanor (MD, PhD; Leeds, UK)
• Simone Ignatova (MD)
• Post-doc Nazre Batool (PhD)
Health Economics
• Professor Lars-Åke Levin (PhD)
• Lektor Martin Henriksson (PhD)
Business Partners
• AMRA AB
• Wolfram MathCore AB

14. Our projects
14
NILB
n = 110
LIFE & 4LIFE
n = 60
HiFi
n > 100
•fat
•fibrosis
•iron
•inflammation
•OATPB1
•OATPB3
•MRP2
•MRP3
digiNILB
n > 150
Steatosis
Non-Alcoholic
Steatohepatitis
(NASH)
Fibrosis
Cirrhosis &
Cancer
SCAPIS
n = 400

15. 15
Diagnostic tool or demonstrator (4LIFE)
The technology would
add:
• Degree of
fibrosis/cirrhosis
• Liver function
• Iron concentration
• Body fat composition
• The visualization
Multimodal MR-method that can replace standard biopsy plus measure liver function

16. Aim
16
• Overall aim is to provide an early assessment of the
value of the diagnostic tool (demonstrator referred to
as 4LIFE technology)
• With a focus on HCC in this particular application
• Generic consideration of early assessments of the
diagnostic tool under development

17. Economic evaluation
17

18. Decision problem
18
• Liver function (lab tests)
• Tumor burden
• ECOG
• Age
HCC patients
candidates for
operation
4LIFE strategy
Clinical practice
• 4LIFE technology
• Clinical practice
Costs and
outcomes?
Costs and
outcomes?

19. Evaluation considerations
19
HCC patients
candidates for
operation
4LIFE
strategy
Clinical
practice Diagnostic
information
Diagnostic
information
Management
decision
Management
decision
implemented
treatments
Implemented
treatments
Patient outcomes
Healthcare costs
Patient outcomes
Healthcare costs
Information available with
each diagnostic strategy
Type of treatment chosen for
patient based on diagnostic
information
Clinical outcomes associated
with chosen treatment
strategies
Patient long-term health outcomes
and healthcare costs associated with
treatment strategies
Evaluation of management sequences

20. Evaluation considerations
20
HCC patients
candidates for
operation
4LIFE
strategy
Clinical
practice Diagnostic
information
Diagnostic
information
Management
decision
Management
decision
implemented
treatments
Implemented
treatments
Patient outcomes
Healthcare costs
Patient outcomes
Healthcare costs
Information available with
each diagnostic strategy
Type of treatment chosen for
patient based on diagnostic
information
Clinical outcomes associated
with chosen treatment
strategies
Patient long-term health outcomes
and healthcare costs associated with
treatment strategies
Evaluation of management sequences

21. Evaluation considerations
21
HCC patients
candidates for
operation
4LIFE
strategy
Clinical
practice Diagnostic
information
Diagnostic
information
Management
decision
Management
decision
implemented
treatments
Implemented
treatments
Patient outcomes
Healthcare costs
Patient outcomes
Healthcare costs
Information available with
each diagnostic strategy
Type of treatment chosen for
patient based on diagnostic
information
Clinical outcomes associated
with chosen treatment
strategies
Patient long-term health outcomes
and healthcare costs associated with
treatment strategies
Evaluation of management sequences

22. Evaluation considerations
22
HCC patients
candidates for
operation
4LIFE
strategy
Clinical
practice Diagnostic
information
Diagnostic
information
Management
decision
Management
decision
implemented
treatments
Implemented
treatments
Patient outcomes
Healthcare costs
Patient outcomes
Healthcare costs
Information available with
each diagnostic strategy
Type of treatment chosen for
patient based on diagnostic
information
Clinical outcomes associated
with chosen treatment
strategies
Patient long-term health outcomes
and healthcare costs associated with
treatment strategies
Evaluation of management sequences

23. Evaluation considerations
23
HCC patients
candidates for
resection
4LIFE
strategy
Clinical
practice Diagnostic
information
Diagnostic
information
Management
decision
Management
decision
implemented
treatments
Implemented
treatments
Patient outcomes
Healthcare costs
Patient outcomes
Healthcare costs
Information available with
each diagnostic strategy
Type of treatment chosen for
patient based on diagnostic
information
Clinical outcomes associated
with chosen treatment
strategies
Patient long-term health outcomes
and healthcare costs associated with
treatment strategies
Evaluation of management sequences

24. The decision-analytic model
24
Patient candidates
for operation
4LIFE
strategy
Clinical
practice
Resection
RF
Transplant
TACE
Resection
RF
Transplant
TACE
Long-term
consequences of
each treatment
• Costs
• Quality of life
• Survival
Alive
Dead
TACE: Transcatheter chemoembolization
RF: Radiofrequency ablation

25. Data sources
25
Patient candidates
for operation
4LIFE
strategy
Clinical
practice
Resection
RF
Transplant
TACE
Resection
RF
Transplant
TACE
Long-term
consequences of
each treatment
• Costs
• Quality of life
• Survival
Alive
Dead
Data from Swedish
quality register
TACE: Transcatheter chemoembolization
RF: Radiofrequency ablation

26. Data sources
26
Patient candidates
for operation
4LIFE
strategy
Clinical
practice
Resection
RF
Transplant
TACE
Resection
RF
Transplant
TACE
Long-term
consequences of
each treatment
• Costs
• Quality of life
• Survival
Alive
Dead
Literature based
TACE: Transcatheter chemoembolization
RF: Radiofrequency ablation

27. Data sources
27
Patient candidates
for operation
4LIFE
strategy
Clinical
practice
Resection
RF
Transplant
TACE
Resection
RF
Transplant
TACE
Long-term
consequences of
each treatment
• Costs
• Quality of life
• Survival
Alive
Dead
Expert opinion
TACE: Transcatheter chemoembolization
RF: Radiofrequency ablation

28. Data inputs
28
Clinical practice* 4LIFE**
Counts Proportion Proportion
Ablation 252 0.255 0.217
Resection 324 0.328 0.406
Transplant 151 0.153 0.153
TACE 261 0,264 0.225
Total 988 1.000 1.000
Treatment decision
*Based on current clinical practice decision making
**Based on estimates from experts that 15% of
ablation and TACE patients will be subjected to
resection
“Treatment effect”
based on expert
opinion

29. Data inputs
29
Survival prognosis after treatment
Estimated survival from the Swedish registry of tumors in the liver and bile ducts.
Potential “treatment
effect” due to
improved surgery

30. Data inputs
30
• Literature review ongoing – not much data available
(conditional on treatment given)
– Investigating the possibility to use registries
– Assuming a QoL decrement of 30 % compared with general
population in the present analysis
Quality of life

31. Data inputs
31
Costs
Parameter SEK
Cost of 4LIFE diagnostic procedure 5000
Cost of liver resection the year of resection with 4LIFE 150000
Cost 2nd and subsequent years after liver resection with 4LIFE 20000
Cost of liver resection the year of resection with clinical practice 150000
Cost 2nd and subsequent years after liver resection with clinical practice 20000
Cost of RFA the year of RFA with 4LIFE 50000
Cost 2nd and subsequent years after RFA with 4LIFE 10000
Cost of RFA the year of RFA with clinical practice 50000
Cost 2nd and subsequent years after RFA with clinical practice 10000
Cost of TACE the year of TACE with 4LIFE 45000
Cost 2nd and subsequent years after TACE with 4LIFE 10000
Cost of TACE the year of TACE with clinical practice 45000
Cost 2nd and subsequent years after TACE with clinical practice 10000
Cost of transplant the year of transplant with 4LIFE 800000
Cost 2nd and subsequent years after transplant with 4LIFE 30000
Cost of transplant the year of transplant with clinical practice 800000
Cost 2nd and subsequent years after transplant with clinical practice 30000

32. Data inputs
32
Costs
Parameter SEK
Cost of 4LIFE diagnostic procedure 5000
Cost of liver resection the year of resection with 4LIFE 150000
Cost 2nd and subsequent years after liver resection with 4LIFE 20000
Cost of liver resection the year of resection with clinical practice 150000
Cost 2nd and subsequent years after liver resection with clinical practice 20000
Cost of RFA the year of RFA with 4LIFE 50000
Cost 2nd and subsequent years after RFA with 4LIFE 10000
Cost of RFA the year of RFA with clinical practice 50000
Cost 2nd and subsequent years after RFA with clinical practice 10000
Cost of TACE the year of TACE with 4LIFE 45000
Cost 2nd and subsequent years after TACE with 4LIFE 10000
Cost of TACE the year of TACE with clinical practice 45000
Cost 2nd and subsequent years after TACE with clinical practice 10000
Cost of transplant the year of transplant with 4LIFE 800000
Cost 2nd and subsequent years after transplant with 4LIFE 30000
Cost of transplant the year of transplant with clinical practice 800000
Cost 2nd and subsequent years after transplant with clinical practice 30000

33. Data inputs
33
Costs
Parameter SEK
Cost of 4LIFE diagnostic procedure 5000
Cost of liver resection the year of resection with 4LIFE 150000
Cost 2nd and subsequent years after liver resection with 4LIFE 20000
Cost of liver resection the year of resection with clinical practice 150000
Cost 2nd and subsequent years after liver resection with clinical practice 20000
Cost of RFA the year of RFA with 4LIFE 50000
Cost 2nd and subsequent years after RFA with 4LIFE 10000
Cost of RFA the year of RFA with clinical practice 50000
Cost 2nd and subsequent years after RFA with clinical practice 10000
Cost of TACE the year of TACE with 4LIFE 45000
Cost 2nd and subsequent years after TACE with 4LIFE 10000
Cost of TACE the year of TACE with clinical practice 45000
Cost 2nd and subsequent years after TACE with clinical practice 10000
Cost of transplant the year of transplant with 4LIFE 800000
Cost 2nd and subsequent years after transplant with 4LIFE 30000
Cost of transplant the year of transplant with clinical practice 800000
Cost 2nd and subsequent years after transplant with clinical practice 30000

34. Model settings in base case
34
• Model a 65 year old with HCC
• Cost and outcomes discounted at 3%
• “Treatment effect” incorporated through changed
decision making (not on outcome of surgery)

35. Results (preliminary)
35
Strategy
4LIFE evaluation Clinical practice Incremental
Cost (SEK) 284055 266192 17863
Life years 5.104 4.952 0.152
QALYs 2.932 2.846 0.087
Cost/Life year 117371
Cost/QALY 206011

36. Sensitivity scenarios (general investigation of
parameter importance)
36
Incremental
costs
Incremental
QALYs ICER
Base case 17863 0.087 206011
“Treatment effect” on resection (mortality HR 0.80) 24407 0.258 94679
Importance of long-term costs (0 from year 2) 15327 0.087 176764
Importance of long-term costs (x2 from year 2) 22932 0.087 264506
Survival prognosis (20% increase in mortality risk) 17257 0,087 214676
General QoL 0.5 17863 0.062 288416
Cost of 4LIFE diagnostic (x2) 22863 0.087 263676

37. Sensitivity scenarios (treatment effect
parameters)
37
HR Incr cost Incr QALY ICER
1.00 17862 0.087 206011
0.95 19342 0.125 154518
0.90 20918 0.166 125787
0,85 22601 0.210 107434
0.80 24407 0.258 94679
0.75 26350 0.309 85285
0.70 28450 0.364 78068
0
50000
100000
150000
200000
250000
0.6 0.7 0.8 0.9 1
ICER
HR survival
Survival post resectionProportion resected
Proportion Incr cost Incr QALY ICER
0 5000 0 NA
5 9288 0.029 321342
10 13475 0.058 234844
15 17863 0.087 206011
20 22150 0.116 191595
0
50000
100000
150000
200000
250000
300000
350000
0 5 10 15 20 25 30
ICER
Proportion of TACE/RP patients shifted to resection

38. Conclusion early evaluation
38
• Many and large uncertainties (no surprise given the
early evaluation approach)
• A structure do define what we need to look for in
order to assess the technology appropriately
– How do treatment decisions change
– Long-term prognosis of patients
• Based on cost-effectiveness there may still be a case
for this technology in clinical practice
• Need to resolve many of the uncertainties
• Where do we go from here?

39. Discussion
39

40. The full value of the technology?
40
• Liver surgery (resection in HCC)
• Liver transplantation
• Early onset of liver disease
• Liver donation
Our first attempt to assess value in terms of cost-effectiveness is partial
in the sense that there are many potential applications.
Research councils (and developers) are interested in the overall value.
Unclear to me to address this broader question. Is our partial evaluation
a small piece in a larger puzzle?

41. Incorporation in clinical practice and
treatment effect
41
• Do we need to be more explicit about treatment effect (proportion that go to
resection and outcome of resection)?
– Much focus is not on getting an understanding of baseline values, thresholds for abnormality etc in
developing the diagnostic tool
– Imply we can more “accurately” distribute patients (according to thresholds) to different treatments
– Incorporating the post-resection MR scan for prediction?
– Moving from our endpoint driven epidemiological type of models to organ level models (systems
biology)
MR scan Surgery MR scan

42. Sum up
42
• Indication of cost-effectiveness and which parameters that may be worth
researching
• Bridge from basic research to clinical practice to policy decision
• Should we do partial cost-effectiveness analyses early on or should other
assessments of value be considered (PET-scans, PCI etc)

43. 43