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Diagnostics Working Group 29 October 2004 Mark Perkins Partnership • Partner academic and national institutions: 20 workplans and activity descriptions All India Institute of Medical Sciences Brazilian National TB Network Gambia MRC Industry Partners Institute for Tuberculosis Research IUATLD Johns Hopkins Center for TB Research KIT (Royal Tropical Institute) KIT (Korean Institute of TB) London School Hyg & Trop Med MSF Mycobacteria Reference Lab, NL Partners in Health PATH PHRI Prince Leopold Institute of Tropical Medicine RELACTB Research Insitute of Tuberculosis (JATA) Russian Research Center for Molecular Diagnostics SA MRC Sequella Foundation Statens Serum Institut Stanford Center for TB Research Swedish Institute for Infectious Disease Control TBRU TDR TRC US CDC Div TB Elimination US CDC National Center for Infectious Diseases US FDA US NIH-NIAID ZAMBART • Industry partnership: ~ 50 groups • Other fora: CDC/NIH, EC, KIT, Wellcome, IUATLD What’s missing? • Coordinated strategy for tool-directed research • Coordination of field site strengthening • Diagnostic trial registration and standardization • Consensus on phase IV research priorities Designated funding needed for these activities DOTS expansion has not improved case detection rates No of countries implementing DOTS 250 100 Global case 90 notification rate 80 (All forms of TB) 70 60 50 40 30 20 10 0 Total number of countries 200 150 100 50 00 20 99 19 98 19 97 19 96 19 95 19 94 19 93 19 92 19 91 19 19 Year 90 0 Global CNR Countries Clear need to enhance case detection to attain global TB control targets Source: WHO Report 2003: Global Tuberculosis Control: surveillance, planning, financing. WHO, 2003. Inefficiency of global TB case detection: 2004 16% 56% 28% AFB+ detected AFB+ undetected AFB negative Total 1,421,467 2,465,533 4,910,000 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” Development of new technologies Harvesting the best of both worlds to produce public sector goods Private sector Public sector • Market-driven • Financing • Product focus • Manufacture & Distribution • IP management •Needs driven • Goal-directed R&D •Altruism • Complex project management •Partnership 1900 1950 • Rigid targets/milestones • Marketing Publicprivate partnership •Industry model + •Need-driven •Partnership 2000 FIND will drive diagnostics development from concept to delivery in the health system FIND’s focus Upstream Discovery and research Development Liaise with funders, pharmaceutical and biotech companies, research institutions, academia July 22nd, 2003 Facilitate, co-fund, co-develop Demonstratio n Create network of public and private partners to create effective tests and demonstrate their success Development Proof of principle Evaluation Downstream Regulatoryquality lab & field trials FIRST BOARD MEETING Geneva, Switzerland Liaise with funders, multi-lateral agencies, NGOs,health ministries, and agencies like GDF and GFATM Demonstration Evaluation Product in box Market access and distribution Efficacy Data Large-scale projects Effectiveness measuring Data feasibility and impact on disease control programs Policy Virtual development Manage portfolio of development, evaluation, and demonstration projects Develop Evaluate Demonstrate Specimen Bank Specimen/strain Bank Technical support to NTPs Strain Bank Trial site support Usage Guidelines Market Analysis Mathematical modelling Standardized protocols Regulatory harmonization Access assistance Operational research Enabling Infrastructure Provide intellectual and material infrastructure for diagnostics development Priority needs for TB diagnostics Purpose Case Detection Drug susceptibility testing Latent TB Infection Test Indications Proposed Priority • Detect pulmonary TB with high bacterial load (SS+) #1 • Detect pulmonary TB with low bacterial load (SS -, Cx +) #2 • Detect extra-pulmonary and pediatric TB #3 • Detect MDR-TB for treatment #4 • Detect MDR-TB for surveillance #7 • Detect LTBI for surveillance #5 • Detect LTBI for treatment #6 Segmentation - diagnostic question vs. health system level diagnostic question health system level 1. Detection 2. Resolution 3. Surveillance • Who shall be treated? • Is patient responding • Change treatment for failure? • Are programs effective? • Are there new strains? • Is the strain resistant? • QC procedures & policies • strain typing Central lab District lab Health Center (Clinic) • fill detection gap • resolve unclear cases • resistance testing • Yes–No answer • medical monitoring RESOLUTION faster than culture ! DETECTION more sensitive than smear ! July 22nd, 2003 FIRST BOARD MEETING Geneva, Switzerland • easy & robust lab procedures • support for multiple health problems • universal platforms • dedicated POC devices • minimal skill requirements 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 Tests that are significant incremental improvements over existing tools • 2-day lab-free culture replacement • Specific predictor of progression from LTBI • Improved microscopy • Simplified or speeded culture • Simplified or speeded DST POSITIVE • POC smear supplement NEGATIVE 2003 2004 2005 2006 2007 2008 Improving sputum microscopy 1- Fluorescence 6- Phenol 2- Polycarbonate filters 7- UPS 3- Immunosedimentation 8- NaOCl 4- Magnetic beads 9- CB-18 5- Chitin 10- Silica TDR RFA Immunomagnetic separation of mycobacteria from sputum for improved fluorescent microscopy Programmatic use of improved microscopy - differential impact on well and poorly functioning laboratories 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 Point of care Skin test Sequella Ag detection Chemogen, GoSensor, Chembio, Lionex, DOE, KIT, Proteomesystems Aerosol Scensive, Mensanna, Rapid Biosensors Microscopy Baldingerst, O’Connell, Xytron Ab detection Corixa/IDRI, SSI, NYU, VictoriaU, CSU Molecular Cepheid, Takara, GenProbe, Roche, Eiken, Idaho, Innogenetics, Investogen Phage Biotec, Microphage, Sequella Culture BD, Biotest, Salubris District lab Colorimetric solid media Detection speed LJ 28d BACTEC 10d TK 14d Contamination Mycobacterial growth Phage replication assay for detection or DST TB bacilli Actiphage INFECTION TREATMENT WITH VIRUSOL Phage start to replicate in cells NEUTRALISATION OF VIRUSOL AND ADDITION OF SENSOR CELLS Sensor cells POSITIVE NEGATIVE PLATING OF MIXTURE IN A PETRI DISH AND OVERNIGHT INCUBATION Sensor cells Sensor cells Sensor cells Sensor cells Upstream FIND’s focus Discovery and research Development Liaise with funders, pharmaceutical and biotech companies, research institutions, academia Evaluation Downstream Demonstration Create network of public and private partners to create effective tests and demonstrate their success Market access and distribution Liaise with funders, multi-lateral agencies, NGOs,health ministries, and agencies like GDF and GFATM Exploiting technology for the public good From concept to affordable delivery in the health system Proof of principle Research Development Evaluation Facilitate, co-fund, co-develop Regulatoryquality lab & field trials Product in box Demonstration Efficacy Data Large-scale projects measuring Effectiveness Data feasibility and impact on disease control programs Policy 2004-2008 Portfolio 2004 Planning Antigen detection Simple NAAT Development Phage detection MGIT case detection TB serology Evaluation Demonstration Market 2005 2006 2007 2008 Phage detection Simple NAAT Antigen detection TB serology Simple NAAT Antigen detection Simple NAAT Antigen detection Phage DST TK media MPT64 patch test TK media MPT64 patch test Phage detection TK media TB serology MPT64 patch test MGIT case detection Simple NAAT Antigen detection T-spot TB QuantiferonGold MGIT DST Phage DST T-spot TB Quanitiferon Gold MGIT DST MGIT case detection T-spot TB Quanitiferon Gold Phage detection TK media TB serology MPT64 patch test MGIT case detection MGIT case detection MGIT DST Phage DST Quanitiferon Gold T-spot TB Urban NAAT Phage detection TK media TB serology MPT64 patch test