Diagnostics Working Group

29 October 2004Mark Perkins

Partnership

All India Institute of Medical Sciences

Brazilian National TB NetworkGambia MRCIndustry PartnersInstitute for Tuberculosis ResearchIUATLDJohns Hopkins Center for TB

ResearchKIT (Royal Tropical Institute)KIT (Korean Institute of TB) London School Hyg & Trop MedMSFMycobacteria Reference Lab, NL

Stanford Center for TB Research

Swedish Institute for Infectious Disease Control

TBRUTDRTRCUS CDC Div TB EliminationUS CDC National Center for

Infectious DiseasesUS FDAUS NIH-NIAIDZAMBART

• Partner academic and national institutions: 20 workplans and activity descriptions

• Industry partnership: ~ 50 groups

Partners in Health PATHPHRIPrince Leopold Institute

of Tropical MedicineRELACTBResearch Insitute of

Tuberculosis (JATA)Russian Research

Center for Molecular Diagnostics

SA MRCSequella FoundationStatens Serum Institut

• Other fora: CDC/NIH, EC, KIT, Wellcome, IUATLD

• Coordinated strategy for tool-directed research

• Coordination of field site strengthening

• Diagnostic trial registration and standardization

• Consensus on phase IV research priorities

What’s missing?

Designated funding needed for these activities

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.

16%

28%56%

AFB+ detectedAFB+ undetectedAFB negative

2,465,533

4,910,000

1,421,467

Inefficiency of global TB case detection: 2004

Total 8,797,000

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”

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

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

July 22nd, 2003 FIRST BOARD MEETINGGeneva, Switzerland

diagnostic question healthsystem level

1. Detection• Who shall be treated?• Is patient responding

2. Resolution• Change treatment for failure?

• Is the strain resistant?

3. Surveillance• Are programs effective?• Are there new strains?

Central lab• QC procedures & policies

• strain typing

District lab • fill detection gap • resolve unclear cases

• resistance testing

Health Center

(Clinic)

• Yes–No answer

• medical monitoring

• easy & robust lab procedures • support for multiple health problems• universal platforms

• easy & robust lab procedures • support for multiple health problems• universal platforms

• dedicated POC devices• minimal skill requirements

• dedicated POC devices• minimal skill requirements

Segmentation - diagnostic question vs. health system level

DETECTIONmore sensitive than smear !

RESOLUTIONfaster than

culture !

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

Improving sputum microscopy

6- Phenol

7- UPS

8- NaOCl

9- CB-18

10- Silica

1- Fluorescence

2- Polycarbonate filters

3- Immunosedimentation

4- Magnetic beads

5- Chitin

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

Point of care

District lab

Aerosol

Ag detection

Molecular

Skin test

Microscopy

Ab detection

Phage

Culture

Scensive, Mensanna, Rapid Biosensors

Chemogen, GoSensor, Chembio, Lionex, DOE, KIT, Proteomesystems

Sequella

Corixa/IDRI, SSI, NYU, VictoriaU, CSU

Baldingerst, O’Connell, Xytron

Biotec, Microphage, Sequella

BD, Biotest, Salubris

Cepheid, Takara, GenProbe, Roche, Eiken, Idaho, Innogenetics, Investogen

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

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

2004-2008 Portfolio

  2004 2005 2006 2007 2008

PlanningAntigen detection Simple NAAT        

Development

Phage detectionMGIT case detectionTB serology

Phage detectionSimple NAAT Antigen detectionTB serology 

Simple NAAT Antigen detection

Simple NAAT Antigen detection

Evaluation

Phage DSTTK mediaMPT64 patch test 

TK media MPT64 patch test 

Phage detectionTK media TB serologyMPT64 patch test  MGIT case detection  

Simple NAATAntigen detection

Demonstration

T-spot TBQuantiferonGoldMGIT DST

Phage DST T-spot TBQuanitiferon GoldMGIT DSTMGIT case detection

T-spot TB Quanitiferon Gold

Phage detectionTK media TB serologyMPT64 patch test   MGIT case detection  

Market    

MGIT case detection MGIT DSTPhage DST 

Quanitiferon Gold T-spot TBUrban NAAT  

Phage detectionTK media TB serologyMPT64 patch test