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

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“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

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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

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PERFORMANCE OF AN ORAL HIV RAPID TEST

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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

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A BALANCING ACT

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DEPLOYABILITY, PERFORMANCE & PREVALENCE

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• 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

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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

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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

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test

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test

Vx“Without Diagnostics, Medicine is Blind”

Alain Mérieux

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THANK YOU