Unifying research and coverage decisions: How the assessment required can be informed.

1. Unifying research and coverage decisions:
How the assessment required can be informed
Claire McKenna
K Claxton, S Palmer, L Longworth†, L Bojke, S Griffin,
M Soares, E Spackman, J Youn†
Centre for Health Economics, University of York, UK
†Health Economics Research Group, Brunel University, UK
9th HTAi Annual Meeting Bilbao June 23-27, 2012

2. Allocation and research decisions
A number of conceptually distinct but simultaneous decisions must be made:
 Which technology should be adopted into clinical practice given the existing
evidence base and the uncertainty surrounding outcomes and resource use?
 Is additional evidence required to support the use of the technology?
- How uncertain are the expected benefits?
- Does this uncertainty matter (will it change the adoption decision)?
- How much does it matter (consequences of getting it wrong)?
 What type of evidence would be most valuable?
 Which research designs would be worthwhile?
 When to approve the technology?
- Early approval? Can the evidence be provided with approval?

3. Policy options: Approve, Reject, OIR, AWR
Approve Could impact the prospects of acquiring further evidence
Reject Could restrict patient access to promising new technologies
Additional policies: overcomes the problems associated with making coverage decisions
under uncertainty
Only in research ‘No’ decision until further evidence establishes value
(OIR) - Only approved for use within the context of suitable
research study
Approve with research ‘Yes’ decision until further research is completed
(AWR) and guidance is established

4. What assessments are needed?
 Expected cost-effectiveness
 Irrecoverable costs
– Costs committed by approval that cannot be recovered
• Capital costs of long lived equipment (training and learning)
• Initial losses (negative NHE) offset by later gains
• Significance depends on whether initiation of treatment can be delayed
 Value of additional evidence
 The need for evidence, type of evidence, design of research
 Uncertainty that cannot be resolved by research but only over time
 Are the benefits of early approval greater than the opportunity costs?
Establish the circumstances when an OIR or AWR scheme may be an
appropriate policy option

5. Checklist of assessment
The sequence of assessment can be summarised as a simple 7-point checklist
†For technologies not expected to be cost-effective, point 4 becomes ‘Is the research possible without approval?’

6. Possible pathways:

7. Case study: EECP for chronic stable angina
 Enhanced external counterpulsation (EECP) is a non-invasive procedure used
to treat chronic stable angina
 Primary outcome is the symptomatic relief of angina symptoms
 EECP has large initial upfront costs of treatment (£4,347 per patient), which are
irrecoverable once treated Long inflatable pressure cuffs are
inflated and deflated to increase
 EECP as adjunct to standard therapy vs. blood flow to the coronary arteries
standard therapy alone
 One RCT showed evidence of improved HRQoL
at 12 months
 Uncertain whether HRQoL benefits are
sustained beyond 12 months

8. Point 1 - Is the technology expected to be cost-effective?
 Assessment of effectiveness, potential for harm and costs over a patient time horizon
 Assessment and judgement at points 1 and 2 of the checklist:
- Does not lead directly to guidance
- Determines subsequent pathway
Incremental mean costs £4,744
Incremental mean QALYs 0.2446 Treatment decision:
maximum expected net health effects
ICER for EECP £19,392
Cost-effectiveness at threshold (per QALY gained):
£10,000 £20,000 £30,000
Net health effects (NHEs):
EECP £70,071 £144,887 £219,702
Standard therapy £72,369 £144,738 £217,107

9. Point 2 – Are there significant irrecoverable costs?
5,000
Cumulative incremental NHE of EECP over the patient time horizon
Cumulative incremental NHE at population
0
0 5 10 15 20 25 30 35 40 45 50
level for EECP, QALY
-5,000
-10,000
-15,000
-20,000
Technology time horizon
-25,000
Time, years

10. Point 2 – Are there significant irrecoverable costs?
5,000
Cumulative incremental NHE of EECP over the patient time horizon
Cumulative incremental NHE at population
0
0 5 10 15 20 25 30 35 40 45 50
level for EECP, QALY
-5,000
Capital cost spread over 10 years
Capital cost incurred in year 1
-10,000
-15,000
-20,000
Technology time horizon
-25,000
Time, years

11. Point 3 – Does more research seem worthwhile?
i. How uncertain is a decision to approve or reject
ii. Do the likely consequences of uncertainty justify further research
• NHE that could be gained if it could be resolved immediately
• Upper bound on potential benefits of more research
• ‘No’ can lead directly to guidance
Cost-effectiveness threshold at £20,000 per QALY
Incremental NHE Probability Expected
Treatment QALY (£m) cost-effective consequences,
QALY (£m)
EECP 1,405 (28.1) 0.428
9,287
(185.7)
Standard care - 0.572

12. Point 3 – Does more research seem worthwhile?
0.45
Probability of no losses = 0.43
0.40
0.35
0.30
Probability
0.25 Expectation across the distribution of consequences
= 9,287 QALYs (£180m)
0.20
EVPI = Maximum value of research = £180m
0.15
0.10
0.05
0.00
0 [0,5000] [5000,10000] [10000, 15000] [15000,20000] [20000,25000] [25000,30000] [30000,35000] [35000,40000] [40000,45000]
Consequences, QALY

13. Point 4 - Is research possible with approval?
i. Type of evidence needed?
ii. Can the research be conducted while approved?
• Importance of parameters (values that change the decision)
• Uncertainty in possible values (how likely to change)
• NHE that are to be gained (expected consequences)
• Assessment and judgement at point 4
- Does not lead directly to guidance
- Determines whether AWR or OIR are possibilities
Expected consequences (QALYs)
0 1,000 2,000 3,000 4,000 5,000 6,000 7,000 8,000 9,000 10,000
(1) Incremental HRQoL benefits in first year 8,127
(2) Probability of sustaining HRQoL benefits in
subsequent years (group of elicited parameters)
3,860
(3) 2-year probability of repeat EECP sessions 0
Overall decision uncertainty (EVPI) 9,287

14. Point 5 – Will other sources of uncertainty resolve over time?
i. Other sources of uncertainty
• Changes in price (technology and comparators)
• New technologies entering
• Other evidence becoming available
Types and categories of guidance for EECP that could ultimately result from
assessments up to point 6
Assessment 1 2 3 4 5 6 7 Guidance
17 Yes Yes Yes Yes No Yes Yes AWR 4
18 Yes Yes Yes Yes No Yes No OIR 4
19 Yes Yes Yes Yes No No - Approve 6
24 Yes Yes Yes No No Yes Yes Approve 9
25 Yes Yes Yes No No Yes No OIR 6
26 Yes Yes Yes No No No - Approve 10

15. Point 6 – Are the benefits of research greater than the costs?
i. Will the research be conducted? iii. How much uncertainty will be resolved?
ii. When will it be available? iv. Impact of other sources (point 5)
Expected consequences, £
£0 £40,000,000 £80,000,000 £120,000,000 £160,000,000 £200,000,000
0.00
Costs of research,
0.10 £1.5m (75 QALYs)
0.20
Probability of research
0.30
0.40
0.50
0.60
0.70
0.80
0.90 Research reports
9 8 7 6 5 4 3 2 1 year delay immediately
1.00
0 2,000 4,000 6,000 8,000 10,000
Expected consequences, QALY

16. Point 7 – Are the benefits of approval greater than the costs?
 The final point on the checklist requires a comparison of the benefits of
approval and early access and the opportunity costs of approval
• Value of research forgone as a consequence
• Irrecoverable costs committed by approval
- Capital costs (equipment, facilities, training and learning)
- Initially negative NHE (when treatment decisions can be changed)
Types and categories of guidance for EECP that could ultimately result:
Assessment 1 2 3 4 5 6 7 Guidance
17 Yes Yes Yes Yes No Yes Yes AWR 4
18 Yes Yes Yes Yes No Yes No OIR 4
24 Yes Yes Yes No No Yes Yes Approve 9
25 Yes Yes Yes No No Yes No OIR 6

17. Point 7 – Are the benefits of approval greater than the costs?
 The final point on the checklist requires a comparison of the benefits of
approval and early access and the opportunity costs of approval
• Value of research forgone as a consequence
• Irrecoverable costs committed by approval
- Capital costs (equipment, facilities, training and learning)
- Initially negative NHE (when treatment decisions can be changed)
Types and categories of guidance for EECP that could ultimately result:
Assessment 1 2 3 4 5 6 7 Guidance
17 Yes Yes Yes Yes No Yes Yes AWR 4
18 Yes Yes Yes Yes No Yes No OIR 4
24 Yes Yes Yes No No Yes Yes Approve 9
25 Yes Yes Yes No No Yes No OIR 6
Is research possible
with approval?

18. Point 7 – Are the benefits of approval greater than the costs?
 The final point on the checklist requires a comparison of the benefits of
approval and early access and the opportunity costs of approval
• Value of research forgone as a consequence
• Irrecoverable costs committed by approval
- Capital costs (equipment, facilities, training and learning)
- Initially negative NHE (when treatment decisions can be changed)
Types and categories of guidance for EECP that could ultimately result:
Assessment 1 2 3 4 5 6 7 Guidance
17 Yes Yes Yes Yes No Yes Yes AWR 4
18 Yes Yes Yes Yes No Yes No OIR 4
24 Yes Yes Yes No No Yes Yes Approve 9
25 Yes Yes Yes No No Yes No OIR 6
Is research possible
with approval?

19. Technologies with significant irrecoverable costs
- Research is not possible with approval
0.0
An OIR or Approve boundary (EECP)
Probability that research is conducted
Sufficient condition for Approve
0.2
0.4
Necessary condition for OIR
0.6
4-year design
0.8 3-year design
2-year design
1-year design
1.0
0 1 2 3 4 5 6 7 8 9
Time for research to report, years

20. Evaluation of alternative research designs
- Research is possible with approval
OIR k = £20,000 AWR
£100,000 £40,000
Population ENBS x £1,000
Population ENBS x £1,000
£90,000 n* = 1,540 n* = 1,540
£35,000
£80,000 n* = 1,000
£30,000 n* = 900
£70,000
n* = 920 n* = 580
£60,000 £25,000
£50,000 n* = 720 £20,000 n* = 520
£40,000 4-year follow-up
£15,000 4-year follow-up
£30,000 3-year follow-up
£10,000 3-year follow-up
£20,000 2-year follow-up
2-year follow-up
£10,000 1-year follow-up £5,000
1-year follow-up
£0 £0
0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400 0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400
Sample size (n) Sample size (n)

21. Conclusions
 Policy analysis based on value of information analysis can be used to
consider the value of:
i. being able to conduct research while a technology is approved;
ii. the trade-off between the expected NHEs to current patients from
early access and the NHEs to future patients from more research;
 Understanding the relationship between the time taken for research to report
and the value of the evidence can help inform:
i. investments which might make research findings available quickly
ii. the trade-off implicit in the choice of alternative research designs
iii. those areas where research must be reported quickly to be of value
Claxton et al. (2012) Uncertainty, Evidence and Irrecoverable Costs: Informing Approval,
Pricing and Research Decisions for Health Technologies. CHE Research Paper 69.
http://www.york.ac.uk/che/publications/in-house/