Diagnostics Working Group 29 October 2004 Mark Perkins

Partnership 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 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 Partner academic and national institutions: 20 workplans and activity descriptions Industry partnership: ~ 50 groups 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 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 countries implementing DOTS DOTS expansion has not improved case detection rates Year Total number of countries Global case notification rate (All forms of TB) Countries Global CNR Source:WHO Report 2003: Global Tuberculosis Control: surveillance, planning, financing. WHO, 2003.

2,465,533 4,910,000 1,421,467 Inefficiency of global TB case detection: 2004 Total8,797,000

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 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 MEETING Geneva, Switzerland FIND will drive diagnostics development from concept to delivery in the health system Liaise with funders, pharmaceutical and biotech companies, research institutions, 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 focusUpstreamDownstream DevelopmentEvaluation Demonstratio n Development Facilitate, co-fund, co-develop Evaluation Regulatory- quality lab & field trials Demonstration Large-scale projects measuring feasibility and impact on disease control programs Proof of principle Product in box Efficacy Data Effectiveness Data Policy

Virtual development Enabling Infrastructure Provide intellectual and material infrastructure for diagnostics development Manage portfolio of development, evaluation, and demonstration projects DevelopEvaluate 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 MEETING Geneva, Switzerland diagnostic question health system 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 DETECTION more sensitive than smear ! RESOLUTION faster 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

Improving sputum microscopy 6- Phenol 7- UPS 8- NaOCl 9- CB 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 speed LJ28d BACTEC10d TK 14d Colorimetric solid media Contamination Mycobacterial growth

Phage replication assay for detection or DST POSITIVE NEGATIVE

Exploiting technology for the public good From concept to affordable delivery in the health system Research Policy

Portfolio Planning Antigen detection Simple NAAT Development Phage detection MGIT case detection TB serology Phage detection Simple NAAT Antigen detection TB serology Simple NAAT Antigen detection Simple NAAT Antigen detection Evaluation 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 Demonstration 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 Market MGIT case detection MGIT DST Phage DST Quanitiferon Gold T-spot TB Urban NAAT Phage detection TK media TB serology MPT64 patch test