Molecular Biology and Pathology:

rivals or companions

Viewpoint of the IVD industry

Alex Lefevre Head of Market Access and Medical Affairs Execo IVD beMedTech November 18th, 2017

Agenda

Introduction

General Info

EU IVD Regulation

beMedTech

Future steps

Agenda

Introduction

General Info

EU IVD Regulation

beMedTech

Future steps

Three major trends in 2030 will directly impact diagnostics

MORE PATIENT CENTRIC GREATER USE OF DATA EMPHASIS ON ACTING EARLY

August 3rd, 2015

Thomas

Grogan, M.D.

American

professor,

pathologist

and founder

of Ventana

Medical

Systems, Inc.

Hematoxylin & Eosin (H&E) Stain

Malignant melanoma, Clark’s level 4 (3.76mm total depth)

Immunohistochemical (IHC) Staining Results

Positive for MART-1/Melan-A, SOX10

MART-1/Melan-A SOX10

AJCC Clinical Staging

Stage IIIb: T3a, N2c, MO associated with ~75% recurrence

Genomic Testing Results

10 non-synonymous mutations including BRAF V600K

Patient at UCLA Receiving Immunotherapy

Actually he’s cured and fly-fishing again

Molecular

Biology

AND

Pathology

__________________________________________________________________

Quality

demands R

eg

ula

tory

ma

na

ge

me

nt

Shorter TAT

Big Data

Lab consolidation Reduced

budgets Inc

rea

sin

g

vo

lum

es

Qualified staffing shortages

Increasing

complexity

Process control

NSCLC treatment becomes complex Diagnostics are critical

Non-squamous Cell Squamous Cell

ROS1+ ALK+ EGFR Mut PD-L1 ≥

50% TPS

PD-L1 1-

49% TPS

PD-L1 <

1% TPS

PD-L1 ≥

50% TPS

PD-L1 1-

49% TPS

PD-L1 <

1% TPS

Crizotinib

1L treatment

Maintenance

(responders only)

2L treatment

Chemo

Ram

Alectinib or

ceritinib

Osimertinib Chemo Ram

T790M+ T790M-

1st or 2nd gen

EGFR-TKI Pembro Pembro Chemo Chemo Chemo bev

Pembro, nivo

or atezo

Pembro or

atezo Chemo Ram

Bevacizumab

(if eligible)

Pemetrexed

(if eligible)

Nivo or atezo Atezo

Adapted from presentation by Sylvie Lantejoul at ELCC 2017

Agenda

Introduction

General Info

EU IVD Regulation

beMedTech

Future steps

15 * Wolcott,J. & Goodman,C. (2009). The Value of Laboratory Screening and Diagnostic Tests for Prevention and Healthcare Improvement. Health Technology Report. The Lewin Group. * *DOI:10.1371/journal.pone.0149856

_________________________________________________________________

The Value of Diagnostics IVD’s underestimated*

Hospital costs Healthcare decision-making

5%

In on average 75% of patients, IVDs are used**

17

Labmedicine landscape in Belgium Share of IVDs is 1,5% of total HC budget

Health care budget

± 25,6 bilj € (2018)

Labmedicine budget

1,5 bilj € (5,3 %)

_________________________________________________________________

IVD testing budget

± 380 milj €

(25 %of labmedicine

budget)

18

_________________________________________________________________

Labmedicine in Belgium Budgets

Ref. gestand. Verslag Klinische Biologie 2017

1,5% of total

HC budget

11% of total

labmedicine budget

5,3% of total

HC budget

Anatomical Pathology:

2016: + 0,9% 159.072 k€. Prestations:+ 0,5%.

2017: 171.936 k€. (Ambulant: 113.833 k€ /Hospitalized: 58.103 k€)

Genetic centers:

2016: + 13,4% 49.639 k€. Prestations: + 3,4%. 2017: 52.596 k€. (Ambulant: 47.819 k€ /Hospitalized: 4.777 k€)

19

Anatomical Pathology/Genetics in Belgium Budgets

Budget

2018 ???

Budget

2018 ???

20

Reimbursement of new IVD tests? A question?

How many new tests in anatomopathology/molecular biology

have been reimbursed in the last 5 years?

_________________________________________________________________

21

__________________________________________________________________

Complex IVD Reimbursement process A glimmer of hope

22

__________________________________________________________________

Complex IVD Reimbursement process But …

Need for a efficient decision process with

agenda, timelines, evidence based and health

economic decision outcome.

23

_________________________________________________________________________

Complex IVD Reimbursement process No clear procedure

The nomenclature

Clinical Biology

o Article 3

o Article 18

o Article 24

o Article 24bis

o Article 33 bis

Pathology anatomy

o Article 32

Genetic labs

o Article 33

Nomenclatuur

Technisch Geneeskundige Raad/Conseil Technique Médical

• De T.G.R. beslist in zijn plenaire vergadering over de voorstellen die door de 6 beperkte werkgroepen worden voorbereid : • algemeen • chirurgie • huisartsgeneeskunde • interne geneeskunde • klinische biologie • medische beeldvorming

• Gemengde ad hoc werkgroepen (vb. klinische biologie + interne geneeskunde + genetica) zijn mogelijk. In de werkgroepen kunnen experten worden uitgenodigd.

24

_________________________________________________________________________

IVD Reimbursement How to do it?

Template

• Goal reimbursement file (PICO)

• Description pathology/indication

• Epidemiological data

• Value dossier diagnostic test

• Literature analysis • Clinical evidence

• Economical evidence

• Financing and reimbursement proposal in Belgium + Benchmark with other European countries

• Health economic model (budget impact analysis + cost-effectiveness)

• Conclusions and recommendations

26

_________________________________________________________________________

Important questions for the recommendation and adoption of new diagnostic tests (NICE, UK)

Does using the test change clinical decisions?

Are there improved health outcomes?

What is the impact on system resources (lab, facilities, staff, as well as money)?

Even with some evidence of effectiveness, can the test be implemented in our system/ hospital?

Will clinicians use the recommended cut-off?

Rule-out vs rule-in, and risk management

28

ICER = difference in effect (current treatment vs new treatment)

difference in cost (current treatment vs new treatment)

Improved health outcomes? How to evaluate it? the incremental cost-effectiveness ratio

IVD Reimbursement – Molecular biology/Pathology

How to do it?

29

_________________________________________________________________________

IVD Reimbursement – Molecular biology/Pathology

How to do it?

30

_________________________________________________________________________

31

The key reason for the gap between the provision and demand for molecular diagnostic testing is a lack of specific funding for the tests. Proposal** A new article 33ter: new “generic” nomenclature codes for tests linked to a drug , defined by TMC 3 generic nomenclature codes: B-1800 B-3000 B-4000 Start: 01 January 2018

A lack of specific funding for these tests A parallel process between CRM and TMC is ongoing

** Anouk Waeytens, National Institute for Health and Disability Insurance Belgium, beMedTech symposium 22/11/2016

Redesign of Care Administrations Belgium currently contains 8 administrations related to HC, but

Agenda

Introduction

General Info

EU IVD Regulation

beMedTech

Future steps

• EU laws on medical devices and in vitro diagnostics (IVDs) is

over 20 years old.

• Not adapted to technical/scientific progress:

- Device/drug combinations

- Companion diagnostics

- Move from hospital to home setting

- E-health and m-health

• EU countries interpret rules differently

• Globalization

• EU public consultation started already in 2008

EU IVD Regulation Drivers for change

35

_________________________________________________________________________

NEW EU IVD Regulation Published on May 5th, 2017 in the Official EU Journal .

EU IVD Directive How was it?

36

New EU IVD Regulation What’s new?

37

38

New EU IVD Regulation The new classification scheme

39

New EU IVD Regulation What will it bring to stakeholders?

40

New EU IVD Regulation Impact on IVD industry (EU)

GDPR (General Data Protection Regulation), 25 May 2018

41

_________________________________________________________________________

The appropriate use of new tests Tests in current use vary in accuracy and potential to improve health outcomes.

* Holtzmann and Watson, 1999

Analytical validity

Clinical validity

Clinical utility

Three categories of test performance .

Clinicians and health care policymakers must consider the accuracy with which a test identifies a patient’s clinical status (clinical validity) and the risks and benefits resulting from test use (clinical utility).

EU IVD Regulation In-house tests/lab-developed tests (LDTs)

Definition and general rules

• An in-house test is an IVD that is ‘manufactured and used within health institutions’

• A health institution is an ‘organisation whose primary purpose is the care or treatment of patients or the promotion of public health’

Obligations of health institutions

• Comply with General Safety and Performance requirements of Annex I

• Confirm compliance with standard EN ISO 15189 of the health institution’s laboratory

• Justify that patient needs are not met by available CE IVD tests

Member States can issue further rules regarding accreditation of and standards for laboratories of health institutions

42

An assay is an entire system Including antibody, detection, instrument and other components

Clinical trials use the entire system and…regulatory agencies approve the entire system

Using only parts of the system and not the entire system carries significant risk…and may lead to poor patient outcomes

• Inappropriate treatment decisions

• Over-treatment and side effects

• Under-treatment and missed opportunities

Vyberg et al. BMC Health Services Research (2015) 15:352

Publications on LDTs vs FDA/CE IVD tests Some Examples

44

Company Confidential – Internal Use Only

46

BC = Base-case

SA = Scenario analysis

Example EGFR Mutation Test Case Individual Patient Probability of Misclassification

NEW: Lab Cost Calculator

50

An apple and an orange are both fruits but different companion versus complementary assay’s

What is a companion diagnostic? Provides predictive information Is required

A companion diagnostic is a test that accurately and reliably detects a

biomarker and in clinical trials has demonstrated the ability to assist in

differentiating patients who will or will not benefit from the

associated drug. It is required for the safe and effective use of the drug.

http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm262327.pdf

What is a complementary diagnostic? Provides predictive information Aids in the drug risk-benefit decision process

A complementary diagnostic aids in the risk-benefit decision process:

it provides information about using a specific drug in the context of a

clinically meaningful risk-benefit difference.

Reena Phillips. Developing Diagnostics: Perspective From the FDA. ASCO 2016 presentation. http://meetinglibrary.asco.org/content/51097?media=vm

Companion required

A must do

Complementary informs

A can do

Companion is required, complementary informs Both provide information about likely patient benefit

A market access study is ongoing on

Complementary Dx in the EU at KULeuven & Vlerick

Agenda

Introduction

General Info

EU IVD Regulation

beMedTech

Future steps

• “Belgische federatie van de industrie van de medische technologieën v.z.w.”, “Fédération belge de l’industrie des Technologies médicales a.s.b.l.”.

• Number of beMedTech members 2017: 208

• 5 ExeCo’s: Group Implants Group Consumables Group Extra-Muros Group Diagnostics Group Medical Equipment & Systems

• Director since 01/01/2017: Marnix Denys

55

56

57

_________________________________________________________________________

Quality has a competitive impact Diagnostics as lever - evaluate the quality of testing (ISO 15189 accreditation)

Classification of causes of diagnostic error related to testing.

58

59

60

_________________________________________________________________________

Pact Medical Technologies Launched on October,5th 2016

1/ Tests in-house new European Directive

2/ Point-of-care testing Primary Care

4/ Next-generation Sequencing roadbook

3/ Reimbursement system for CDx & non CDx

5/ Prevention/screening protocols the role

of IVDs

61

Agenda

Introduction

General Info

EU IVD Regulation

beMedTech

Future steps

Three major trends in 2030 will directly impact diagnostics

MORE PATIENT CENTRIC GREATER USE OF DATA EMPHASIS ON ACTING EARLY

What will happen as healthcare becomes more patient centric?

Storyboard 6

MORE PATIENT CENTRIC

Deeper understanding of disease pathways and mechanisms

What are the implications of more patient-centric healthcare?

Storyboard 6

MORE PATIENT CENTRIC

Deeper understanding of disease pathways and mechanisms

Less… one marker: one disease

Less… therapeutic trial and error

More… personalized treatment based on multiple markers

The value of understanding disease mechanisms

LUNG CANCER

2005 20051

NSCLC 2nd Line 80%

60%

40%

20%

0% 9%

RESPONSE

TO

THERAPY

No biomarkers

OS < 7 mo

The value of understanding disease mechanisms

Storyboard 7

2012 2017

1. Shepherd FA, et al. NEJM 2005; 353 (2): 123–32 (Tarceva)

OS: Overall Survival

80%

60%

40%

20%

0% ~65%

RESPONSE

TO

THERAPY

The value of understanding disease mechanisms

Storyboard 7

20051 20122 2017

80%

60%

40%

20%

0%

9%

RESPONSE

TO

THERAPY

NSCLC 2nd Line

No biomarkers

OS < 7 mo

1. Shepherd FA, et al. NEJM 2005; 353 (2): 123–32 (Tarceva)

2. Rosell R, et al. Lancet Oncol 2012; 13: 239-46 (Tarceva)

NSCLC 1st Line

EGFR mutated

OS > 22mo

OS: Overall Survival

Multiple markers

PFS >18.9 mo

80%

60%

40%

20%

0% ~80%

RESPONSE

TO

THERAPY

The value of understanding disease mechanisms

Storyboard 7

20051 20122 20173

80%

60%

40%

20%

0% ~65%

RESPONSE

TO

THERAPY

80%

60%

40%

20%

0% 9%

RESPONSE

TO

THERAPY

NSCLC 2nd Line

No biomarkers

OS < 7 mo

1. Shepherd FA, et al. NEJM 2005; 353 (2): 123–32 (Tarceva)

2. Rosell R, et al. Lancet Oncol 2012; 13: 239-46 (Tarceva)

3. Ramalingam S, et al. Presidential Symposium I of the ESMO 2017 Congress; September 8 -12; Madrid (3rd Generation)

NSCLC 1st Line

EGFR mutated

OS > 22mo

PFS: Progressive Free Survival

Integrating data from diverse sources is changing healthcare

GREATER USE OF DATA

Each patient’s cancer informs all those cases that will comein the future.

Unprecedented access to vast data sets is changing outcomes

Each patient’s cancer informs all those cases that will come in the future.

ANTICIPATE…

Integration from diverse

sources

Realtime access

Artificial intelligence

engines

Data improving drug

development

Diagnostics Real-World Data

73

__________________________________________________________________

_______

Molecular diagnostics is growing rapidly New innovative technologies as a competitive driver

74

__________________________________________________________________

_______

Next Generation Sequencing Roadmap

08 May 2017 | page 75 | © 2017 Roche | Internal Use Only Not for Distribution

What about liquid biopsy testing? AVENIO ctDNA Analysis Kits

Expanded

Tumor Profiling

Tumor

Profiling

Launching a liquid biopsy portfolio targeting different clinical research applications

AVENIO ctDNA Targeted Kit

Guideline Driven Biomarkers*

17 genes (81 kb)

Lung, Colorectal, Breast, Gastric, Glioma,

Melanoma, Ovarian, Thyroid, Pancreatic

AVENIO ctDNA Expanded Kit

Guideline Driven & Emerging Biomarkers

77 genes (192 kb), includes 17 genes from targeted panel

Lung, Colorectal, Breast, Gastric, Prostate, Glioma,

Melanoma, Ovarian, Thyroid, Pancreatic

AVENIO ctDNA Surveillance Kit

Guideline Driven Biomarkers & Disease Monitoring

197 genes (198 kb), includes 17 genes from targeted panel

Primary: Lung, Colorectal; Secondary: Breast, Gastric, Prostate,

Glioma, Melanoma, Ovarian, Thyroid, Pancreatic

Tumor Burden

Monitoring

CLINICAL RESEARCH

* National Comprehensive Cancer Network. http://www.nccn.org. October 15, 2016

NAVIFYTM

Tumor Board

Data will improve outcomes

Each patient’s cancer informs all those cases that will come in the future.

ANTICIPATE…

Integration from diverse

sources

Realtime access

Artificial intelligence

engines

Data improving drug

development

Better coordination of

care

NAVIFYTM

Tumor Board

Diverse data sources will inform clinical decisions

Each patient’s cancer informs all those cases that will come in the future.

ANTICIPATE…

Integration from diverse

sources

Realtime access

Artificial intelligence

engines

Data improving drug

development

Better coordination of

care

Integration of diverse

data sources

Patients will control access with technologies like Blockchain Technology

Each patient’s cancer informs all those cases that will come in the future.

PATIENTS Will control data access

Medicine, and so Dx, will drive early detection and prevention

EMPHASIS ON ACTING EARLY

It may eventually be possible to

identify those individuals at special

risk of tobacco or diet-associated

cancers, and also those susceptible

to the effects of environmental

contaminants.

” “

World Health Organization / Programs / Genes and Human Diseases / Genes and noncommunicable diseases

http://www.who.int/genomics/public/geneticdiseases/en/index3.html, Oct 16, 2017

IVD industry partnering with Pathologists

beMedTech: active collaboration with pathologists quality charter update pact medical technologies

Roche Diagnostics: partner by going for better reimbursement with Health economic data clinical trials with new upcoming CDx markers partner in showing the value of anatomopathology working together on new innovative products, like multiplexing, NAVIFY, Real World Data,…

80

Roche Oncology Symposium Save the Date: Thursday November 23rd, 2017

82

Doing now what patients need next