StopTB Partnership Forum 25 March 2004 The Future of TB Diagnostics FIND: Foundation for Innovative New Diagnostics Mark Perkins, MD Giorgio Roscigno, MD

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.

TB notification in Zambia, incidence in Lusaka >900/100,000 Disproportionate increase in smear-negative disease <20% notified pulmonary TB pts are smear-pos

DOTS-Plus and the GLC, 2002 Source: WHO 2002 Applications to the GLC under review DOTS-Plus projects Strong candidates to apply to the GLC

 120-year old tools that are difficult to implement  <20% of all cases detected with microscopy and notified  Long delays = morbidity, transmission  Much over and undertreatment in HIV prevalent areas  Resistance clinically diagnosed with long delays  Latent infection tools clumsy and indiscriminate Current TB diagnostic situation

Lack of progress in diagnostics in the developing world Fundamental diagnostic: 1882 Fundamental diagnostic: 2003 Discovery Science Product Development Targets & Reagents Companies & Platforms Performance testing Evaluation & Approval Need & Access Market uptake

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

Facilitating commercial development of diagnostics

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”

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: as defined in FIND Business Plan

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

Portfolio Planning Antigen detection Simple NAAT Development Phage detection Rapid culture TB serology Phage detection Rapid culture Simple NAAT Antigen detection TB serology Rapid culture Simple NAAT Antigen detection Simple NAAT Antigen detection Simple NAAT Evaluation Phage DST Colorimetric culture Active TB skin test Phage DST Colorimetric culture Active TB skin test Phage detection Colorimetric culture TB serology Active TB skin testRapid culture Antigen detection Demonstration LTBI blood test Rapid culture DST LTBI blood test Rapid culture DST Urban NAAT LTBI blood test Urban NAAT LTBI blood test Phage detection Colorimetric culture TB serology Active TB skin test Rapid culture Market Rapid culture DST Phage DST Urban NAAT LTBI blood test Phage detection Colorimetric culture TB serology Active TB skin test

Improving sputum microscopy 5- Phenol 6- UPS 7- NaOCl 8- CB Fluorescence 2- Polycarbonate filters 3- Immunosedimentation 4- Magnetic beads 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

Detection speed LJ28d BACTEC10d TK 14d Colorimetric solid media Contamination Mycobacterial growth

Phage replication assay for detection or DST POSITIVE NEGATIVE

MPT-64 Patch Test

Poor performance of existing tests in limited trials Sens%Spec% 6 different tests (HIV prevalent) different tests (HIV-uninfected) kDa a-crystallin ESAT6 MPT64 Mtb81 CFP10 MPT51 MPT63 MPT70 MTC28 MTB48 MTB8 GroES MPT32 19kDa 65kDa Ag85B Ag85A Ag85C Antigen 84 Rv2394 Rv1368 Rv3390 A60

Skipping a generation of communication technology

Rats help sniff out TB

Aerosol detection - “Electronic Noses” Cyranose 320 detector chip Conducting polymer Advantages: Reusable No cost to operate Multi-use Electronic memory

FIND/TDR antigen detection projects

Nature Seyton, et al. 9/9/2003 “Fluorobodies” with Ab binding loops into GFP Size of commonly used labeling agents

TMA: Gen-Probe PCR: Roche Diagnostic LCR: Abbott Laboratory SDA: Becton Dickinson NASBA: Organon Teknika CPT: ID Biomedical RAM: Hamilton Thorne Invader : Third Wave RAPID TM APT: AG Corp BioChip: Englehardt Inst. Exploiting NAAT 3D gelpad microarrays

M. Tb M. avium M. intracellulare Nil Loop-mediated isothermal amplification Closed system Isothermal Rapid Multiprimer Visible readout Iwamoto et al. J Clin Microbiol. 41:

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

Benefits of rapid and accurate diagnostics PatientDisease controlHealth system cost morbidity family spread transmission cure rates empowers patient empowers MD empowers staff cost of misdiagnosis

The value chain starts with improving existing diagnostic services Incremental improvements in existing tests Point of care replacement for culture or multiplex lab test Simple point of care and new performance lab systems Improved laboratory infrastructure