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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