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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
0123456789
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Withdrawn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.