TDR activities in support of new TB diagnostics

Jane CunninghamMedical Officer

UNICEF/UNDP/World Bank/WHO Special Programmefor Research and Training in Tropical Diseases (TDR)

Tuberculosis Diagnostic Initiative (TBDI) launched by

the WHO Global TB Control Program

Tuberculosis added to TDR's portofolio and TBDI transferred to TDR

Grants from the Bill and Melinda Gates Foundation,

USAID, Rockefeller

FIND launched

FIND/TDR Joint Workplan

TDR is born1975

1997

1998

2001

2003

2004

Historical Background

Shifting Philosophy

TBDIstimulate and facilitate industry to adapt available technologies for new diagnostics rather than the direct funding of competitive product development Conclusion ….. this is not enough Evolution of FIND

FIND SAC•Proposal review•Platform Strategies

Product Development

Technical support:test and site

selection process

Coordinate clinicaltrials of new

diagnostic products

Lead regulatory approval process

Technical support: •Product •Guidelines for appropriate use

TDR Steering

Committee

RFAs

Evidence forImpact:•Mathematical •modelling

•TB Specimen & Strain Bank •Evaluations (serologics, DST, new products)

•Trial site preparedness – GLP, GCP, Monitoring•Standardized •protocols

•Diagnostic •Evaluation •Expert Panel •Convene regulators

Demonstration projects Tech support to NTPsGuidelines forappropriate use

Facilitate procurementOperational research

FIND

TDR

100%

0%

Project TeamDiagnostic Development

Project TeamDiagnostic Development

Discovery

Lab Evaluation Phase II

Clinical TrialsPhase III

Registration

DemonstrationPhase IV

Diagnostic Development Pathway

Discovery

"Bright Ideas Grants Programme" – conduit to screen new technologies and attract new tool developers to the field 2001- 2003

Novel concepts for detecting MTBNovel or improved methods for smear microscopy 28 investigators funded , including 5 industry groups

Approved Projects - $1,884,623

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10

Tool Development

DiscoveryResearchEvaluation

Smear microscopy

Withdrawn

Product Development

Generating evidence base to inform the design of tools with the greatest impact.

Stimulating R&D in diagnostics for TBTB Diagnostics Market Analysis

Quantifying the TB Diagnostic Process

Lima, Peru

Chang Mai, Thailand

Chennai, India

Lusaka, Zambia

4 country field study measuring delays in diagnosis, and the economic impact of the diagnostic process.

1600 newly diagnosed TB patients 1000 Respiratory symptomatics

Mathematical modelling

To predict the impact of new diagnostic tools with varying operational and performance characteristics. Sake de Vlas & Nico Nagelkerke developed a model Main components of the model

TB biology, including extra-pulmonary TB and HIVThe TB diagnostic processOrganization of health care systemHealth-seeking behavior

Mathematical Modelling - 2

Dis1_1

Dis1_2

Dis1_3

Dis1_4

Dis0_2

Dis0_3

Dis4_4 Dis3_4

Dis3_3

Dis2_4

Dis2_3

Dis2_2

Dis0_4

Dis0_1

Death

Cured_1

Cured_2

Cured_3

Cured_4

New infect.

Susceptible

‘Old’ infect.

Not in health system

Under treatment

Informal sector withTB symptoms

Cure

Doctor’s delay,

Diagnostic delay

Patient delay

Partial cure

Drop-out Drop-out

Formal sector with TB symptoms, pre-suspicion

Formal sector,for first TB testing(s)

Patient delay

(Self-) referral

Neg. test

(Self-) referral

Drop-out

Drop-out,

Pos. test, Doctor’s delay,

Diagnostic delay

Pos. test, Doctor’s delay,

Formal sector,for second TB testing(s)

Drop-out, Neg. test

Blue: Depends on TB stage

Poster Session: Oct. 31 - Reference number is PS-593-664-31

Laboratory Based Evaluation

New tools vs. existing tools

Well characterized reference materials are a necessity

TB Specimen and Strain Banks

TB Specimen Bank

Serum, urine, saliva, sputum from TB patients and negative controlsPatients = 1116 (605 TB+; 441 TB-; 343 HIV +; 772 HIV-)Aliquots 8 925Projected No. aliquots = 26 500Updated website info

TB Specimen Bank Collection Sites

Original collection sites, started 1999

MRC, DurbanSouth Africa

MRC, Banjul, The Gambia

Uganda/CWRU Research Collaboration, Kampala, Uganda

Hospital UniversiárioProf. Edgar Santos, Salvador, Brazil

Respiratory Hospital, Winnipeg, Canada

Catalan Health Inst., Barcelona, Spain

New collection sites, starting end 2004

MRC, Durban South Africa

ICDDR,B, Dhaka, Bangladesh

Corporación para Investigaciones Biológicas, Medellín, Colombia

KEMRI, Nairobi, Kenya

Pham Ngoc Thach Hospital, Ho Chi MinhCity, Viet Nam

Instituto de MedicinaTropical "Alexander von Humboldt", Lima, Peru

TB Specimen Bank Requests

0

5

10

15

20

25

-2002 2003 2004

IndustryAcademiaRejection

Requests are considered by a TB Specimen Bank Review Committee

TB Strain Bank

Promote the development of novel technologies for drug susceptibility testing (DST) appropriate for use in disease endemic countries;Facilitate the laboratory evaluation of new (and existing) DST methods and ;Provide reference materials to support quality control and proficiency testing programs in endemic countriesInstitute of Tropical Medicine in Antwerp8 laboratories contributing 239 strainsOperational by Summer 2005

TDR Strain Bank Contributing Laboratories

University of Medicine,Manila, The Philippines10 strains

Kuratorium Tuberkulose in derWelt e.V., Gauting, Germany26 strains

Universidad Autónoma, Barcelona, Spain22 strains

Korean Inst. Of Tuberculosis, Seoul, Republic of Korea21 strains

Inst. Of Tropical Medicine, Antwerp, Belgium120 strains

MRC, Pretoria, South Africa12 strains

Massachusetts State TB Laboratory, Boston, USA16 strains

Instituto Adolfo Lutz, São Paulo, Brazil12 strains

TB Serologic Test Evaluation

Inventory of commercially available serological assays - > 50 Limit evaluation to rapid test formats (24 companies invited) 17 companies have agreed200 HIV+; 200 HIV– serum samples from the TB Specimen Bank (+56 samples for reliability testing)

Scheduled to begin January 2005

Participating Companies 1. ABP Diagnostics Focus Sure Check TB2. Advanced Diagnostics Tuberculosis Rapid Test3. American Bionostica Rapid Test for TB4. Ameritek dBest One Step TB Test5. Chembio TB Stat-Pak II6. CTK Biotech TB Antibody onsiteRapid

Screeing Test Kit7. Hema Diagnostic Rapid 1-2-3 TB Test8. Millenium Biotechnology Immuno-Sure TB Plus9. Minerva Biotech V Scan10.Mossman Associates MycoDot11.Pacific Biotech Bioline TB12.Premier Medical Corporation First Response Rapid TB13.Princeton BioMeditech BioSign M.tuberculosis14.Span Diagnostics TB Spot ver. 2.015.Standard Diagnostics SD Rapid TB16.Syntron Bioresearch QuikPac IV OneStep TB 17.Veda Lab TB Rapid Test

Clinical Trials Support

Phase III Trial Comparing Four Alternative Methods for Drug Susceptibility Testing of MTB. tuberculosis with Gold Standard in SS+ pulmonary Tuberculosis in Lima, Peru

Indirect and direct LJ drug susceptibility testing to rifampinand isoniazid, FASTPlaque RIF-Response test, INNO LiPARif TB test, and indirect MTT drug susceptibility testing.

GLP/GCP training

Diagnostics Expert Evaluation Panel (DEEP)

Diagnostics Expert Evaluation Panel (DEEP)

Goal: To provide best practice guidelines for the evaluation of new diagnostic tests.

Scope: To help those designing evaluations at all levels (from test manufacturers to end users) To guide critical review of published and unpublished evaluations, with a view to selecting or approving tests that have been evaluated and shown to meet appropriate performance targetsTo facilitate the setting of appropriate standards for test evaluation

Demonstration Projects

Guidelines for appropriate use Facilitate procurementOperational research

Near future:

DOTS-plus MGIT demo projects

Improved smear microscopy methods.