The document discusses precision medicine and health technology assessment (HTA) of complementary diagnostics in Europe. It notes that precision medicine is moving from single biomarker tests to complex multi-parameter disease management, but markets have struggled to adopt even simple biomarkers. A new paper published by Epemed identifies additional elements of value for complementary diagnostics beyond traditional HTA considerations like life years gained and cost savings. These include reducing uncertainty, value of hope, and option value of future treatments. The paper recommends changing evidentiary requirements for HTA to consider broader clinical utility and value-based pricing approaches that account for all elements of value.

1. Personalised Medicine in the EU— Evolving
Landscape and New HTA Considerations
3rd Precision Medicine Congress
September 12, 2016, London
Iain Miller, Ph.D.
EPEMED Board Member
Founder Healthcare Strategies Group
Member, NICE Tech Appraisal Committee C
iain@healthcarestrategiesgroup.com
www.epemed.org
Jorge Mestre-Ferrandiz, Ph.D.
Director of Consulting
The Office of Health Economics
jmestre-Ferrandiz@ohe.org

2. Background Context to Presentation
 Precision medicine is on a journey from single marker drug selection
to complex multi-parameter disease management
 Markets have struggled to adopt the current “simple” biomarker-led
paradigm, and a highly heterogeneous global market access
scenario has evolved
 Epemed, a Luxembourg-based non-profit was formed in 2009 to
accelerate adoption of precision medicine products
 In 2016, a diverse group of Epemed stakeholders, working with the
Office of Health Economics, published “The Value of Knowing and
Knowing the Value: Improving the Health Technology Assessment of
Complementary Diagnostics”
 The remainder of this presentation will detail the presenters’
perspective on the current market scenario and the new white paper
9/13/2016 www.epemed.org 2

3. www.epemed.org 3
Overview
• Precision Medicine – where are we today ? (Iain)
• Clinical & product development paradigm
• Market access (UK, broader EU and USA)
• Companion vs complementary diagnostics
• Health Technology Assessment considerations (Jorge)

4. Precision Medicine in the Clinic Today
5
Many concepts courtesy of Clayton Christensen, Harvard University; diagram inspired by Mara Aspinall
•Medicine as
science
• More precise
diagnoses
•Combinations of
markers in NGS
panels inform
disease
management
•Potential for
deployment in
lower cost
settings
•Medicine as art
•Organ-defined
diagnostic
paradigm
•Disease classified
by body’s limited
vocabulary of
symptoms
•Imprecise
diagnoses, even
in chronic
settings (e.g.
automimmune)
20th century paradigm - early 21st century paradigm
4

5. Companion Test Co-Development Paradigm pre-2016
Development
• Pharma identifies single biomarker, partners with Dx company; key focus is FDA PMA mandate
• Diagnostic partner charged to develop and deploy kit-based solution in key geographic settings
• Partners collaborate for 3-5 years to bring combination to market
Clinical Implementation
• Resulting (target-gene specific) test provides strong exclusion (high NPV), but limited ability to
select true responders, especially in medium-long term (modest PPV)
• Rx-Dx combination brings modest benefit (eg. 3 mo. OS), followed by emergence of resistant
clones
• Diagnostic company struggles to deploy “approved” companion test in homogeneous quality-
assured manner across settings
• Sponsors price product at economic willingness-to-pay threshold. Payors struggle to assess
value and accommodate high price points
Comment: Traditional model has delivered only 7 unique FDA-
required tests*, with generally modest impact on global outcomes
* Her2, cKIT, EGFR, KRAS, BRAF, ALK, BRCA 5

6. The “Companion” Test Landscape is Changing…..
Product based, single
biomarker, high NPV/low
PPV
Hybrid product/service
based, multiple biomarkers
high NPV/low PPV ?
Service based,
multifactorial, high
complexity testing,
high NPV/high PPV ?
1998-2012
2012-2016
2017 ---- ?
Historical CDx scenarios
•Roche / Dako / Vysis – Her2
•Amgen / BMS / MS / DxS / Qiagen - KRAS
•AZ / BI / DxS / Qiagen – EGFR
•Pfizer / Abbott - ALK
•GSK / Roche / Biomerieux - BRAF
Contemporary CDx scenarios
•AZ / Myriad. Lynparza / BRCA
•Celgene / Merck – Nanostring
•Foundation Medicine / Clovis
•Foundation Medicine / AZ (HRD testing, DNA repair)
Test panels to
interrogate T cell
recognition,
activation and
infiltration
NGS target-
specific panels,
incl. DNA repair
genes
+
Universal CDx / Baseline test ?
Source: Miller, I, The evolution of high complexity companion testing in targeted and immuno-oncology, Personalized
Medicine journal, Miller Per. Med. (2016) 13(5), 409–414 http://www.futuremedicine.com/doi/pdf/10.2217/pme-2016-0055
6

7. Market Access Today (Oncology) - Highly Heterogeneous
Country Features (Pros/Cons) of Model
+ Available funding, coding for CDx tests
− HTA model not fit for purpose, LDT vs IVD regulatory ambiguity,
reimbursement in flux (PAMA, etc)
+ Cutting edge NICE HTA model with transparent & quantitative criteria;
centralized review
− Some disconnect with budget holders; historical access gaps
+ Centralized INCa review, dedicated funding, expedited access, new
Genomic Medicine 2025 NGS plan (12 hubs)
− Onco-only, local service orientation, no preference for regulated products
+ Centralized review, guaranteed funding (if on drug label), new NGS
coverage (from July 1)
− Modest test funding, local testing req. (protectionism)
+ Some Managed Entry program leadership (AIFA-mainly Rx)
− Lack of central coordination, regional access disparities, variable quality
+ Some central HTA review, NICE model under consideration
− Funding gaps, prevailing “pharma pays” paradigm
Key Sources: CRUK (2015) and European Personalized Medicine Association (Epemed), IMS
Some Observations:
• High degree of deployment variability, spotty NGS coverage
• Domestic protectionism in US, France and Germany (effectively must
test in-country)
• Funding & access gaps in several countries (e.g. 41% of eligible UK
solid tumour patients were not tested in 2014)
• HTA models not well suited to emerging multi-marker, combination
therapy paradigm
• Patients in only 6 countries had access to > 50% of the 49 new
oncology medicines launched from 2010-14
7

8. Complementary vs Companion Tests
• Checkpoint drug class has mix of companion and complementary tests:
• Keytruda NSCLC approval October 2015: companion diagnostic
• Opdivo NSCLC, approval October 2015: complementary diagnostic
• Tecentriq Urothelial approval May 2016: complementary diagnostic
• In 2016 HTA framework analysis, Epemed adopts broader definition: “tests for the
purposes of risk assessment, diagnosis, prognosis, monitoring, and guiding
therapeutic decisions”
• Historically, companion tests defined by FDA as “tests necessary for the safe and effective use
of a drug”
• In late 2015, FDA felt need to define new class of “complementary diagnostic” to capture role of
PD-L1 testing in immuno-oncology : “tests which enrich for response, but not deemed
necessary for selection”
8

9. The Value of Knowing and Knowing the Value
9

10. The Value of Knowing and Knowing the Value
Agenda
• Motivation and objectives
• Elements of value for complementary
diagnostics
• Case studies
• Policy Recommendations
10

11. The Value of Knowing and Knowing the Value
Motivation
1. A growing recognition that medical diagnostics are used in a
wide range of clinically different applications as
complements to other medical inputs
2. Concern that traditional health technology assessment
(HTA) does not appropriately recognise or reward the value
of diagnostics
• Need to broaden the concept of diagnostics beyond
companion diagnostics:
 “Complementary diagnostics”
• Diagnostics provide value to patients beyond health gain and
cost-saving: they can reduce uncertainty about benefit:
 “Value of knowing”
11

12. The Value of Knowing and Knowing the Value
Objectives of OHE/EPEMED White
Paper
• To identify key issues facing the HTA of
complementary diagnostics in Europe
• To provide coherent and consistent terminology for
the definition of diagnostics and the elements of
value
• To define options for addressing challenges and
barriers
• To recommend approaches for dealing with them
12

13. The Value of Knowing and Knowing the Value
Elements of value for
complementary diagnostics
13

14. The Value of Knowing and Knowing the Value
“Traditional” elements of HTA
1. Life years gained
2. Improvements in patient quality of life
3. Cost-savings within the healthcare system (also
called “cost-offsets”)
 1 + 2 = quality-adjusted life year (QALY
 1 + 2 + 3 (+ cost of technology) = assess the cost
effectiveness of the technology
4. Productivity: value of the patient’s time either when
receiving medical care or related to the impact of
absenteeism or presenteeism due to illness
14

15. The Value of Knowing and Knowing the Value
Expanded elements of value
5. Nonmedical cost-savings outside the healthcare
sector, such as transport costs and family caregiving
6. Reduction in uncertainty - additional value from
knowing a technology is more likely to work
7. Value of hope - willingness to accept greater risk
given a chance for a cure
8. Real option value - the value of benefiting from
future technologies due to life extension
9. Insurance value - psychic value provided by
invention of an innovative medical product and by the
accompanying financial risk protection afforded by a
new treatment
10.Scientific spillovers - value due to other
innovations that become possible once a new
technology has been proven to work
15

16. The Value of Knowing and Knowing the Value
Some comments
• Ten elements of value for complementary diagnostics:
largely independent and additive, and aggregable at a
societal level
• However, distinct conceptual measures could be measured
with the same instrument
• Any specific assessment of value should not double-count
effects
• Questions about the weighting, measurability, and
commensurability of the elements are separate issues, and
are not addressed in this White Paper
• Identified several other, less recognised, elements
related to the value of information
• Can apply to medical technologies more generally and
may not be as closely linked to diagnostics as is the
reduction in uncertainty apparent with companion
diagnostics
16

17. The Value of Knowing and Knowing the Value
Case studies (1)
17

18. The Value of Knowing and Knowing the Value
Case studies (2)
18

19. The Value of Knowing and Knowing the Value
Policy recommendations (1)
Change in evidentiary requirements:
• Evidence of clinical utility: more comprehensive
perspective
• Source of evidence: assess the use of “coverage with
evidence development” agreements
Change in the reimbursement to value-based pricing:
• Reimbursement of complementary diagnostics should
account for the all the elements of value
• Cost-effectiveness can be adapted and/or augmented to
consider additional elements of value - contingent valuation
of other specific elements such as the value of reducing
uncertainty or the value of hope
• Explore how to divide the value (between diagnostic and
therapy, when there is one) to promote dynamic efficiency
19

20. The Value of Knowing and Knowing the Value
Policy recommendations (2)
Incentives to uptake of complementary
diagnostics
• Monitor the uptake of complementary
diagnostics, with routine collection and
publication of data
• Ongoing, repeated validation of diagnostics,
leveraging technological enhancements
Equity issues
• Measure barriers and challenges across EU
• Understand the implications of the different
perspectives (health care or societal) on HTA
processes
20