1. The document discusses issues around assessing the value of potentially transformative gene therapies using existing health technology assessment (HTA) methods. It notes that while HTA requirements may be inadequate, some modifications could help address highly uncertain emerging therapies. 2. It analyzes recent examples of gene and cell therapies approved in Europe and a mock appraisal by NICE of a hypothetical CAR T-cell therapy. This suggests existing methods could apply but uncertainty needs careful handling and innovative payment mechanisms may have an important role. 3. The document emphasizes that more thinking is needed around addressing relevant uncertainty, using appropriate discount rates and thresholds, and incorporating innovative payment mechanisms like outcomes-based payments for gene and cell therapies.

1. Professor Adrian Towse
Director of the Office of Health Economics
HTA and Gene Therapy Issues Panel
Are Existing HTA Requirements Inadequate for
Establishing Value for Potentially Transformative
Gene Therapies? Yes, but…

2. ISPOR Glasgow November 2017
I want to draw on two publications…

3. ISPOR Glasgow November 2017
Nine Regenerative Medicines Approved in EU
Chondro
Select
Glybera MACI Provenge Holoclar Imlygic Strimvelis Zalmoxis Spherox
TISSUE GENE Comb
TIP
CELL TISSUE GENE GENE CELL Comb
TIP
Orthop Metab Orthop Onco Opthal &
Transplant
Onco Immuno Transplant Orthop
2009 2012 2013 2013 2015 2015 2016 2016 2017
Norm.
MA
Excep.
MA
Excep.
MA
Norm.
MA
Cond.
MA
Norm.
MA
Norm.
MA
Cond.
MA
Norm.
MA
Orphan Orphan Orphan Orphan
TiGenix
(BE)
UniQure
(NL)
Vericel
(USA)
Dendreon
(USA)
Chiesi
(IT)
Amgen
(USA)
GSK
(UK)
MolMed
(IT)
CO.DON
AG (DE)
Withdrawn (or withdrawal announced) or suspended
Tissue: Tissue Engineered ; Gene: Gene Therapy; Cell; Cell Therapy ; Comb: Combined ;
Cond.: conditional; Excep. Exceptional circumstances ;
MA; Marketing Authorisation. Adapted from Mahalatchimy and Faulkner. University of Sussex. ESRC
REGenableMED project with additional OHE research.

4. ISPOR Glasgow November 2017
The NICE CAR T-cell review exercise
• NICE ‘mock appraisal’ of a hypothetical regenerative
medicine product CAR (chimeric antigen receptor) T-cell
therapy for treating B-cell acute lymphoblastic leukaemia
(NICE, 2016; Hettle et al., 2016)
.
NICE, 2016. Exploring the assessment and appraisal of regenerative medicines
and cell therapy products. London: National Institute of Health and Care Excellence.
Hettle, R., Corbett, M., Hinde, S., Hodgson, R., Jones-Diette, J., Woolacott, N., Palmer, S., 2016. Exploring the
assessment and appraisal of regenerative medicines and cell therapy products. CRD/CHE University of York.
Benefits and Costs of
the two TPPs
TPP1: Bridge to
stem cell
transplant
TPP2: Curative
intent
Assumed individual patient
level incremental QALY
gain
7.46 10.07
Assumed price (acquisition
cost)
£356,100 £528,660

5. ISPOR Glasgow November 2017
The NICE CAR T-cell review exercise: OHE
comments1 (in green)
NICE report concludes that:
1. The existing appraisal methods and decision framework
are applicable to regenerative medicines. This is using a
stylised example designed to fit the existing approach.
2. Quantification of decision uncertainty was key in decision
making. The approach needs to concentrate on
uncertainty that can be reduced, not uncertainty per se.
3. Where uncertainty is substantial, innovative payment
mechanisms may play an important role and facilitate
timely patient access. We agree.
4. Choice of discount rate is extremely important and has a
big impact on the ICER. We agree.

6. ISPOR Glasgow November 2017
Strimvelis NICE HST review (October 2017)
• Strimvelis: severe combined immune deficiency
(SCID) in children
• Highly Specialised Treatment process
• NICE HST Threshold £100K per QALY plus
multiplier up to 3 for 10-30 QALYs
• QALYs gained 14.0 and 19.6 – uplift 1.4/1.96
• 3.5% discount rate
• Plausible ICER £120.5K and £12.1K per QALY
• NICE recommends as cost effective

7. ISPOR Glasgow November 2017
GSK inks money-back guarantee on $665K
Strimvelis, blazing a trail for gene-therapy pricing
According to MIT Technology Review, GSK will offer the one-
time treatment with a money-back guarantee. Priced at
594,000 euros ($665,000), it’s among the most expensive
therapies in the world. But it’s also a cure for severe
immunodeficiency stemming from a lack of adenosine
deaminase (ADA-SCID), rather than an ongoing treatment as
other rare disease drugs are.
“The drug has to deliver what you say or we don’t pay,” Luca
Pani, director general of the Italian Medicines Agency, told
the publication. “If it does not work, they will return the
money.”
Source: Tracy Staton, FiercePharma, 9 August 2016

8. ISPOR Glasgow November 2017
• Health gain is health gain, irrespective of disease or patient
• Evidence that disease severity matters (Shah 2007)
• EoL matters – NICE EoL criteria applied in the NICE case study:
• Survey evidence supporting EoL specifically is mixed (Shah 2016)
• QALY constant proportional trade-off may not apply (Garau et al. 2011)
• Prospect Theory: patient / citizen perspective can change (Raisel et al. 2005)
• Once treated, the patient is no longer at the end of life
• The higher threshold could be applied over the first few years following curative
treatment (via QALY weighting), with the normal threshold used beyond this
• Evidence of a value of a cure premium delivering a lot of QALYs?
• Tension with severity concept – EEPRU work (Rowen et al, 2016)
• But evidence of value of risk reduction through physical availability of treatment
(Lakdawallah et al. 2017)
End of Life (EoL) criteria / premium for a cure?

9. ISPOR Glasgow November 2017
Uncertainty & Net Health Effects (NHEs)
The ‘investment profile’ over the patient’s lifetime
Breakeven
reflects
proximity of
ICER to
threshold
High up-
front cost
Source: Hettle et al., 2016

10. ISPOR Glasgow November 2017
OHE’s Review: Uncertainty & NHEs
• The York Report uses population NHEs to illustrate:
• (i) total decision uncertainty (the value of perfect information);
• (ii) the ‘investment profile’ over the patient’s lifetime.
Total decision uncertainty = “an expected upper bound to the
benefits of more research”
• But this does not:
• Indicate the expected value of further research
• Consider the cost of conducting further research
• Explore the feasibility of conducting further research prior to
use
• Need to address relevant uncertainty

11. ISPOR Glasgow November 2017
NICE CAR T-cell review exercise
Scenario ICER Probabili
ty cost-
effective
Decision
recommended?
Base case £50,906 50.7% No
Discount of 10% on base
case acquisition cost
£45,131 64.2% Borderline/ No
Payment for patients with
remission only
£45,708 63.9% Borderline/ No
Discount of 10% on base
case price with lifetime
leasing
£45,502 87.2% Assumed
Borderline/ Yes

12. ISPOR Glasgow November 2017
Summary comments
• Gene therapy is making progress –slowly
• Comprehensive reimbursement arrangements
are not in place
• NICE review exercise shows that good planning
can be done
• Needs to be more thinking about:
• Handling uncertain evidence
• Innovative payment mechanisms including outcomes-
based payments
• Relevant threshold
• Appropriate discount rate

13. ISPOR Glasgow November 2017
References
Garau, M., Shah, K.K., Mason, A.R, Wang, Q., Towse, A. and Drummond, M. (2011) Using
QALYs in cancer: A review of the methodological limitations. Pharmacoeconomics. 29(8), 673-
685.
Hettle, R. et al., 2016. Exploring the assessment and appraisal of regenerative medicines and
cell therapy products. CRD/CHE University of York.
Lakdawallah D., et al. 2017. The insurance value of medical innovation. Journal of Public
Economics 145; 94–102
Marsden and Towse, 2017. Exploring the Assessment and Appraisal of Regenerative Medicines
and Cell Therapy Products: Is the NICE Approach Fit for Purpose? OHE Consulting Report.
Marsden et al., 2017. Gene Therapy: Understanding the Science, Assessing the Evidence, and
Paying for Value. Office of Health Economics.
NICE, 2016. Exploring the assessment and appraisal of regenerative medicines and cell therapy
products. London: NICE
NICE, 2017. Strimvelis for treating severe combined immunodeficiency caused by adenosine
deaminase deficiency [ID926]: Evaluation consultation: 1
Raisiel E. et al (2005). Can Prospect Theory Explain Risk-Seeking Behaviour by Terminally Ill
Patients? Medical Decision Making: 25; 609-613
Rowen D, et al. (2016). Eliciting societal preferences for weighting QALYs for burden of illness
and end of life. Medical Decision Making 36(2) 210-222
Shah K (2009) Severity of illness and priority setting in healthcare: a review of the literature.
Health Policy 93:77–84
Shah K. (2016) Does Society Place Special Value on End of Life Treatments?. In: Round J. (eds)
Care at the End of Life. Adis, Cham.

14. ISPOR Glasgow November 2017
Thank You
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Professor Adrian Towse at atowse@ohe.org
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