Personalised Medicine in the EU— Evolving Landscape and New HTA Considerations

Personalised Medicine in the EU— Evolving Landscape and New HTA Considerations

3rd Precision Medicine CongressSeptember 12, 2016, London

Iain Miller, Ph.D.EPEMED Board MemberFounder Healthcare Strategies GroupMember, NICE Tech Appraisal Committee [email protected]

www.epemed.org

Jorge Mestre-Ferrandiz, Ph.D.Director of ConsultingThe Office of Health [email protected]

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

05/01/2023 www.epemed.org 2

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)

Precision Medicine in the Clinic Today

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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

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Companion Test Co-Development Paradigm pre-2016Development• 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

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

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http://www.futuremedicine.com/doi/pdf/10.2217/pme-2016-0055

Market Access Today (Oncology) - Highly HeterogeneousCountry 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 2010-147

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”

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The Value of Knowing and Knowing the Value

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Agenda• Motivation and objectives• Elements of value for complementary

diagnostics• Case studies• Policy Recommendations

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Motivation1. 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”

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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

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Elements of value for complementary diagnostics

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“Traditional” elements of HTA1. Life years gained2. Improvements in patient quality of life3. Cost-savings within the healthcare system (also called

“cost-offsets”)

Þ 1 + 2 = quality-adjusted life year (QALY Þ 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

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Expanded elements of value5. Nonmedical cost-savings outside the healthcare

sector, such as transport costs and family caregiving6. Reduction in uncertainty - additional value from

knowing a technology is more likely to work7. Value of hope - willingness to accept greater risk given a

chance for a cure8. Real option value - the value of benefiting from future

technologies due to life extension9. 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

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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

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Case studies (1)

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Case studies (2)

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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” agreementsChange 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

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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 enhancementsEquity issues• Measure barriers and challenges across EU• Understand the implications of the different

perspectives (health care or societal) on HTA processes

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Presentations & Public Speaking

Personalised Medicine in the EU— Evolving Landscape and New HTA Considerations