StopTB Partnership Forum25 March 2004

The Future of TB Diagnostics

FIND: Foundation for Innovative New DiagnosticsMark Perkins, MD

Giorgio Roscigno, MD

Clear need to enhance case detection to attain global TB control targets

Clear need to enhance case detection to attain global TB control targets

No of countriesimplementingDOTS

DOTS expansion has not improved case detection rates

0

50

100

150

200

250

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

0

10

20

30

40

50

60

70

80

90

100

Year

Total number of countries

Global casenotification rate(All forms of TB)

Countries

Global CNR

Source: WHO Report 2003: Global Tuberculosis Control: surveillance, planning, financing. WHO, 2003.

TB notification in Zambia, 1974 - 2000

0

5000

10000

15000

20000

25000

30000

35000

40000

45000

50000

1974 1976 1978 1980 1982 1984 1986 1988 1990 1992 1994 1996 1998

•incidence in Lusaka >900/100,000•Disproportionate increase in smear-negative disease•<20% notified pulmonary TB pts are smear-pos

DOTS-Plus and the GLC, 2002

Source: WHO 2002

Applications to the GLC under review

DOTS-Plus projects

Strong candidates to apply to the GLC

120-year old tools that are difficult to implement

<20% of all cases detected with microscopy and notified

Long delays = morbidity, transmission

Much over and undertreatment in HIV prevalent areas

Resistance clinically diagnosed with long delays

Latent infection tools clumsy and indiscriminate

Current TB diagnostic situation

Lack of progress in diagnostics in the developing

world

Fundamental diagnostic: 1882

Fundamental diagnostic: 2003

Discovery Science

Product Development

Targets & Reagents

Companies & Platforms

Performance testing

Evaluation & Approval

Need & Access

Market uptake

1900 1950 2000

Development of new technologies

Public sector

Private sector Public-private partnership

•Market-driven

•Product focus

•IP management

•Goal-directed R&D

•Complex project management

•Needs driven

•Altruism

•Partnership

•Industry model +

•Need-driven

•Partnership

•Financing

•Manufacture & Distribution

•Rigid targets/milestones

•Marketing

Harvesting the best of both worlds to produce public sector goods

Facilitating commercial development of diagnostics

Recent history of public sector TB diagnostic development

• Years of denial: 1975 to 1996 “Microscopy is all we need”

• Years of waiting: 1997 to 2003 “Facilitating industry will provide the tools”

• Years of action: 2004 to 2009 “Medical need – evidence – partnership”

July 22nd, 2003 FIRST BOARD MEETINGGeneva, Switzerland

FIND will drive diagnostics development from concept to delivery in the health system

Liaise with funders, pharmaceutical and biotech companies, researchinstitutions, academia

Create network of public and private partners to create effective tests and demonstrate their success

Liaise with funders, multi-lateral agencies, NGOs,health ministries, and agencies like GDF and GFATM

Market access and distribution

Discovery and research

FIND’s focusUpstream Downstream

Development Evaluation Demonstration

Development

Facilitate,co-fund,

co-develop

Evaluation

Regulatory-quality

lab & fieldtrials

DemonstrationLarge-scale

projectsmeasuring

feasibility andimpact on

disease control programs

Proof of principle

Product in box

EfficacyData

EffectivenessData Policy

Virtual development

Enabling Infrastructure

Provide intellectual and material infrastructure for diagnostics development

Manage portfolio of development, evaluation, and demonstration projects

Develop Evaluate Demonstrate

Specimen Bank

Strain Bank

Market Analysis

Mathematical modelling

Specimen/strain Bank

Trial site support

Standardized protocols

Regulatory harmonization

Technical support to NTPs

Usage Guidelines

Access assistance

Operational research

Purpose

Case Detection

Drug susceptibility testing

Latent TB Infection

Test Indications

• Detect pulmonary TB with high bacterial load (SS+)

• Detect pulmonary TB with low bacterial load (SS -, Cx +)

• Detect extra-pulmonary and pediatric TB

• Detect MDR-TB for treatment

• Detect MDR-TB for surveillance

• Detect LTBI for surveillance

• Detect LTBI for treatment

Proposed Priority

# 1

# 2

# 3

# 4

# 7

# 5

# 6

Priority needs for TB diagnostics: as defined in FIND Business Plan

POSITIVE

NEGATIVE

Tests that revolutionize patient care or disease control

• POC smear replacement

• POC culture replacement

• 2-day high-TP sensitive lab test for case detection +/- DST for urban centers

• 2-day lab-free culture replacement

• Specific predictor of progression from LTBI

Tests that are significant incremental improvements over existing tools

• Improved microscopy

• Simplified or speeded culture

• Simplified or speeded DST

• POC smear supplement

2004 20082003 200720062005

2004-2008 Portfolio

  2004 2005 2006 2007 2008

PlanningAntigen detection Simple NAAT        

Development

Phage detectionRapid cultureTB serology

Phage detectionRapid cultureSimple NAAT Antigen detectionTB serology 

Rapid cultureSimple NAAT Antigen detection

Simple NAAT Antigen detection   Simple NAAT

Evaluation

Phage DSTColorimetric cultureActive TB skin test  

Phage DSTColorimetric culture Active TB skin test

Phage detectionColorimetric culture TB serologyActive TB skin test Rapid culture  Antigen detection

DemonstrationLTBI blood testRapid culture DST

LTBI blood test Rapid culture DSTUrban NAAT

LTBI blood test Urban NAAT

LTBI blood testPhage detectionColorimetric cultureTB serologyActive TB skin test    Rapid culture 

Market   Rapid culture DST Rapid culture DST Phage DST  Urban NAAT  

LTBI blood test Phage detectionColorimetric cultureTB serologyActive TB skin test

Improving sputum microscopy

5- Phenol

6- UPS

7- NaOCl

8- CB-18

1- Fluorescence

2- Polycarbonate filters

3- Immunosedimentation

4- Magnetic beads

Immunomagnetic separation of mycobacteria from sputum for improved fluorescent microscopy

Improving the sensitivity of microscopy with a modified membrane filter method to diagnose pulmonary TB

Multicentric evaluation of a smear microscopy techniques for the detection of acid-fast bacilli in sputum specimens

Evaluation of sputum concentration methods for diagnosis of new pulmonary tuberculosis cases by microscopy

Programmatic use of improved microscopy - differential impact on well and poorly functioning laboratories

TDR RFA

Detection speedLJ 28dBACTEC 10dTK 14d

Colorimetric solid media

Contamination

Mycobacterial growth

TB bacilli

Actiphage

TREATMENT WITH

VIRUSOL

INFECTION

NEUTRALISATION

OF VIRUSOL AND

ADDITION OF

SENSOR CELLS

PLATING OF

MIXTURE IN A

PETRI DISH AND

OVERNIGHT

INCUBATION

Phage start toreplicate in

cells

Sensorcells

Sensorcells

Sensorcells

Sensorcells

Sensorcells

Phage replication assay for detection or DST

PO

SIT

IVE

NE

GA

TIV

E

MPT-64 Patch Test

Poor performance of existing tests in limited trials

Sens% Spec%6 different tests (HIV prevalent) 3-60 52-997 different tests (HIV-uninfected) 16-57 80-96

•38kDa•a-crystallin•ESAT6•MPT64•Mtb81•CFP10•MPT51•MPT63•MPT70•MTC28•MTB48•MTB8

•GroES•MPT32•19kDa •65kDa•Ag85B •Ag85A•Ag85C•Antigen 84•Rv2394•Rv1368•Rv3390•A60

Skipping a generation of communication technology

http://news

Rats help sniff out TB

Aerosol detection - “Electronic Noses”

Cyranose 320 detector chip

Conducting polymer

Advantages:

•Reusable

•No cost to operate

•Multi-use

•Electronic memory

SinghLionex Diagnostics and Therapeutics, GmbH

High speed, portable device for TB-diagnosis: simultaneous detection of antigens and antibodies in clinical samples 2001

Swanson Los Alamos National LaboratoryPheromone-based sensor for detection of Tuberculosis siderophores 2002*

Woodman Cranfield BioMedical Centre

Artificial intelligence and gas-sensor arrays for the rapid detection of mycobacteria in cultures, sputum and breath 2002

McCash Rapid Biosensor Systems Limited Aerosol Immunosensor for TB screening 2002

Antonio Campos-Neto Forsythe, Boston

TB detection assays with recombinant proteins that are replicas of Mtb antigens found in urine of infected hosts 2003

Konstantin LyashchenkoChembio, IncSimple and Rapid Lateral-Flow Test for Antigen Detection in Tuberculosis 2003

Stefan Svenson Swedish Institute for Infectious Diseases

Field adapted rapid diagnosis of tuberculosis by detection of specific carbohydrate antigens in urine and other body fluids 2003

Arend H.J. Kolk Royal Tropical Institute

Development of a lateral flow test for detection of Mycobacterium tuberculosis in sputum from TB patients 2003

Mahavir Singh Lionex Diagnostics

Rapid antigen detection in body fluids of TB patients: Development and clinical evaluation of Lionex High Speed device 2003

M. Cynthia Goh Axela Biosensors Diffraction-based sensing for TB diagnostics 2003

FIND/TDR antigen detection projects

Nature Seyton, et al. 9/9/2003“Fluorobodies” with Ab binding loops into GFP

Size of commonly used labeling agents

TMA: Gen-Probe

PCR: Roche Diagnostic

LCR: Abbott Laboratory

SDA: Becton Dickinson

NASBA: Organon Teknika

CPT: ID Biomedical

RAM: Hamilton Thorne

Invader : Third Wave

RAPIDTM APT: AG Corp

BioChip: Englehardt Inst.

Exploiting NAAT

3D gelpadmicroarrays

M. Tb

M. a

vium

M. in

trace

llular

e

Nil

Loop-mediated isothermal amplification

• Closed system

• Isothermal

• Rapid

• Multiprimer

• Visible readout

Iwamoto et al. J Clin Microbiol. 41: 2616-22

Market access and distribution

Discovery and research

FIND WILL HAVE A FOCUSED SCOPE

FIND’s focusUpstream Downstream

Liaise with funders, pharmaceutical and biotech companies, researchinstitutions, academia

Create network of public and private partners to create effective tests and demonstrate their success

Liaise with funders, multi-lateral agencies, NGOs,health ministries, and agencies like GDF and GFATM

Development Evaluation Demonstration

Development

Facilitate,co-fund,

co-develop

Evaluation

Regulatory-quality

lab & fieldtrials

DemonstrationLarge-scale

projectsmeasuring

feasibility andimpact on

disease control programs

Proof of principle

Product in box

EfficacyData

EffectivenessData

Exploiting technology for the public goodFrom concept to affordable delivery in the health system

Research Policy

Benefits of rapid and accurate diagnostics

Patient Disease control Health system

cost

morbidity

family spread

transmission

cure rates

empowers patient

empowers MD

empowers staff

cost of misdiagnosis

The value chain starts with improving existing diagnostic services

Incremental improvements

in existing tests

Point of care replacement for

culture ormultiplex lab test

Simple point of care and new

performance lab systems

Improved laboratory infrastructure