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Streamlining the bench-to-bedside pathway
P. OLLIARO & R. PEELING
WORKSHOP ON NEW AND INNOVATIVE APPROACHES TO LABORATORY DIAGNOSIS OF ZIKA, DENGUE AND OTHER ARBOVIRUSES
ANNECY 2ND -4TH MAY 2017
1
2
“Without Diagnostics,
Medicine is Blind”
Alain Mérieux
Diagnostic Targets
Product Prototype
Lab & field evaluation
Test adoption
Policy and guidelines for use
Proof of Principle
Technology platform
Valley of Death:
Target ProductProfile
Policy & Uptake 5-7 yrs
R&D: 2-10 years; $ 10-100 million ; R&D + adoption 7 – 12 years
Regulatory Approval: 2-5 yrsUSA:
1. FDA approval
2. laboratory developed test (LDT)
(“home-brew”)
EMA: EU IVD 1998 2017
WHO: prequalification
DIAGNOSTICS: THE BENCH-TO-BEDSIDE PATHWAY – A LINEAR PROCESS
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REMOVING BARRIERS TO ACCESS
4
NO TEST IS PERFECT: TRADE-OFFS ARE NECESSARY
Sensitivity
Access 100 90 80 70
100 100 90 80 70
90 90 81 72 63
80 80 72 64 56
70 70 63 56 49
60 60 54 48 42
50 50 45 40 35
40 40 36 32 28
30 30 27 24 21
20 20 18 16 14
10 10 9 8 7
An Example: Trade-off between Access and Sensitivity with all other parameters being equal:
Test sensitivity Access #infected identified/100
100% 30% 30
90% 90% 81
5
PERFORMANCE OF AN ORAL HIV RAPID TEST
6
Performance Measure*
Professional Use OraQuick Test Performance (2-sided 95% CI**)
Over-the-Counter OraQuick Test Performance (2-sided 95% CI**)
Minimum FDA Recommended Performance
Evaluation Results
Minimum FDA Recommended Performance
Evaluation Results
Sensitivity 98% (lower bound of the 2-sided 95% CI)
99.3% (98.4 - 99.7%)
95% (lower bound of the 2-sided 95% CI)
92.98% (86.64 – 96.92%)
Specificity 98% (lower bound of the 2-sided 95% CI)
99. 8% (99.6 – 99.9%)
95% (lower bound of the 2-sided 95% CI)
99.98% (99.90 – 100%)
* Compared to a blood based HIV test**95%CI = 95% Confidence Interval
• The FDA performed a risk analysis to understand the public and individual health implications of approving a test with these performance characteristics:
– estimated number of people who will purchase and use the test– estimated number of net transmissions averted – do the benefits outweigh the risks?
• A risk assessment model showed that in the first year of use, there would be:
– a net increase of ~4,500 new HIV infections identified among those not aware of their HIV status
– ~ 2,700,000 who would test negative. – ~4,000 transmissions would be averted, outweigh the individual risk of
1,100 people who would have false negative results
• Individual risk remained which prompted FDA to address this risk through messages in the test kit labeling
RISKBENEFIT ANALYSIS
7
A BALANCING ACT
8
DEPLOYABILITY, PERFORMANCE & PREVALENCE
9
• Test performance should be weighted against its deployability and prevalence of condition to be diagnosed
455
1138
2275
3413
4095
95238
475
713
855
378
944
1888
2831
3398
133
331
663
994 1193
0,1 0,25 0,5 0,75 0,9
prevalence of condition
Missed diagnosespopulation = 5,000
98% Sensitivity, 1% coverage
90% Sensitivity, 90% coverage
98% Sensitivity, 25% coverage
90% Sensitivity, 75% coverage
1,0
1,4
2,8
4,0
0,25 0,5 0,75 0,9R
atio
98
% S
e 2
5%
co
vera
ge t
est
/
90
% S
e t
est
% population covered with 90% Se test
Missed diagnoses
10
Diagnostic test • Antigen;
Nucleic acid; Pathogen detection
• Antibody
Diagnosis =±
BiomarkerClinical Signs/ Symptoms
ACCELERATING REGULATORY APPROVAL AND PROGRAMME UPTAKE OF DIAGNOSTICS
Assess risk(regulators)
Assess incremental clinical benefit Assess quality
management system
approval
Economic evaluation:• Cost-minimisation• Cost-effectiveness• Cost-benefit• Cost-utility
+
Policy +
Financing =PROGRAMME
UPTAKE
ROLE OF STAKEHOLDERS:• Developers: industry• Regulators: national,
supranational• Experts/Researchers• Implementers:
laboratories• Users: health
systems/public and private health providers
• Beneficiaries: patients
SPECIAL CHALLENGES WITH INFECTIOUS DISEASES OF EPIDEMIC POTENTIAL
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Inter-epidemic period Inter-epidemic periodOUTBREAK
Ebola:
12 EUA’s *
Zika:15 EUA’s *
(12 molecular + 3 serology)
IVD approved ?
IVD approved ?
Demand
Incentives
*https://www.fda.gov/EmergencyPreparedness/Counterterrorism/MedicalCountermeasures/MCMLegalRegulatoryandPolicyFramework/ucm182568.htm#current
SPECIAL CHALLENGES WITH INFECTIOUS DISEASES OF EPIDEMIC POTENTIAL
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Inter-epidemic period Inter-epidemic periodZIKA OUTBREAK
Demand
Incentives New paradigmNew paradigm
type commercialised EUA EUAL* CE-IVD none (* + pipeline)
NAT 15 10 2 5 2 1
serology 11 3 0 4 2 6
NAT 5 1 1 2 2
serology 4 0 0 2 2 2
ALL 35 14 3 13 8 9
ZIKV
multiplex
M Murtagh reportDISCLAIMER: numbers are indicative; rapidly evolving field
CRITICAL: BIO-BANKS
14
Diagnostic Targets
Product Prototype
Lab & field evaluation
Test adoption
Policy and guidelines for use
Proof of Principle
Technology platform
Target ProductProfile
Samples
Test development & validation; Test performance
L J℞
DIAGNOSIS & TEST-OF-CURECLINICAL PRACTICE, PUBLIC HEALTH, DRUG & VACCINE R&D
test test
J
test
J
test
Vx“Without Diagnostics, Medicine is Blind”
Alain Mérieux
16
THANK YOU