Advanced TB Diagnostic Research

Course on Advanced TB Diagnostic Research McGill University, Montreal Data to scale up: building the evidence base for new diagnostics Michael Kimerling, MD, MPH Michael.Kimerling@gatesfoundation.org July 8, 2013

Disclosure BMGF is a funder to numerous stakeholders, including industry Member of Stop TB Partnership board and Executive Committee Member of the WHO TB STAG Former member of Global Fund TRP and current member of TB Committee to advise Secretariat Bias: that the demonstration of impact (or not) is the ultimate evaluation measure of any development, policy, or country scale-up process July 15, 2013 2011 Bill & Melinda Gates Foundation 2

Outline 1. Review: Product scale-up to impact value chain the challenges of Rubik s cubes 2. Assumptions in diagnostics and laboratory networks that potentially limit scale-up 3. BMGF strategy and approach to diagnostic investments 4. Framework of thinking about a country s evidence pathway for scaling-up to impact 5. Country examples of scale-up evaluation: lessons learned General Brazil South Africa 6. Conclusion and Discussion: Q/A July 15, 2013 2011 Bill & Melinda Gates Foundation 3

Interlocking value chains for product scale-up to impact Evidence for issue of policy guidance Global Country decision makers Evidence before/after scale-up Government / public sector Private sector Funders: MOF, Global Fund, other Regulatory authorities Industry and other funders of R/D Market segmentation and business case for investment Product launch and pricing End-user Patient access and provider behavior July 15, 2013 2011 Bill & Melinda Gates Foundation 4

Slide courtesy of P Glaziou, WHO Meeting on post-2015 targets, Geneva, Feb 2013 1.6%/yr 4%/yr 10%/yr Current rate of decline China, Cambodia 19%/yr W Europe after WWII Elimination

Chronology of TB Control & Research 500 TB Research Funding (Millions US$) 450 400 350 300 250 200 150 100 50 19 33 94 Sequella Vaccine 143 Global Alliance FIND 429 STAG Liquid Culture Media STAG LPAs Years 0 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 WHA Resolution New WHO framework DOTS launched Stop TB Initiative launched Amsterdam Declaration Global Fund Stop TB Strategy Global Plan, 2006-2015 Data from (1) Michaud & Murray. Investing in health R&D, WHO 1996; (2) Nunn & Linkins, WHO/TB/98.248, 1995; (3) Nunn & Prasad, presented in 2001 GFHR; (4) TAG, 2008. 6

source: K Weyer, GLI Annual Meeting Annecy, 2012 Tools in combination early diagnosis & care smear-negative TB rapid resistance detection Year Technology Turnaround time Sensitivity gain Before 2007 ZN microscopy Solid Culture 2-3 days 30-60 days Baseline 2007 Liquid Culture / DST Rapid speciation 15-30 days +10% compared to LJ 2008 Line Probe Assay (1st line, Rif & INH) 2-4 days S+ only 2009 LED-based FM 1-2 days +10% compared to ZN 2009 In house DST (MODS, CRI, NRA) 15-30 days 1 st line only 2010 Xpert MTB/RIF (TB, R resistance) 100 minutes +40% compared to ZN

Policy uptake at country level Rapid uptake SS+ case definition Limited or no uptake Two-specimen strategy Same-day-diagnosis Non-commercial culture and DST methods Gradual uptake LED microscopy Liquid culture and DST Rapid speciation Line probe assay source: K Weyer, GLI Annual Meeting Annecy, 2012

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Issues for this group to consider 1. We are in a paradigm shift for global TB programs: We are moving beyond the microscope stage at the PHC level, and local context will be a significant driver of any new paradigm We do not always have the right assumptions about health systems in considering the adoption of new technologies? We are unlikely to ever be able to rely on a single diagnostic or DX platform to meet all needs: surveillance, confirmation of diagnosis, determination of treatment adequacy (DST) and patient monitoring 2. Lessons from GeneXpert product launch are distinct from in-country issues around adoption and scale-up Despite the number of publised demonstration and feasibility studies, we are still very data poor on impact July 15, 2013 2011 Bill & Melinda Gates Foundation 10

Today's tools for TB control are old tools DIAGNOSTIC VACCINE TREATMENT Sputum smear microscopy Discovered 1882 BCG Developed 1920s 1st-line TB drugs Discovered 1943-1970 Slide courtesy of M. Raviglione, WHO

Implementation requirements for new technologies are tool-specific National Reference Lab Referral Laboratory District Laboratory x 1-4 Requires: - BSL3 - Clean rooms - Highly trained staff - Fewer partners x 3-10 Requires: - Secure premises, electricity - Trained staff Infrastructure Biosafety (infrastruct., training, SOPSs) Equipment service & maint. Supply management Adequate storage Waste management Results reporting and referral Quality Assurance REQUIRED AT ALL LEVELS x 10s Point of Care Requires: - Less intensive training - Effective supervision - Large number of partners involved x 1000s

Is the traditional laboratory network becoming obsolete as we push care into the periphery and create alternative technologies and pathways? Secondary, tertiary and reference level tests Rapid molecular tests Triage tests POC

A differing future paradigm that is context driven? Test 1: Triage POC setting #1 Test 6: Measure of cure or infection Test 2: Triage POC setting #2 Test 5: DST Patient diagnosis and care Test 4: PHC based integrated platform Test 3: Rapid confirmatory test July 15, 2013 2011 Bill & Melinda Gates Foundation 14

Market fragmentation: Diagnostics linked to MDR treatment & SLD costs Only a small portion of the need is treated at all, and potential demand is further reduced by fragmentation Global MDR Enrollments (2011) Total burden level Sources of market fragmentation: Funding source: Donor-supported vs. not donor procurement Regimen: 20+ different drugs across 5 groups indicated by WHO for MDR-TB Technical specifications: varying dosage form and packaging 1. Number of (laboratory-confirmed) MDR-TB patients who started treatment for MDR-TB. World Health Organization; Source: presentation to Global Fund Market Dynamics Group, 2013 (S Mostaghim and A Jones)ho.int/tb/country/data/download/

Further Diagnostics fragmentation - Diagnostics play multiple roles in global health: no single tool is adequate to cover full spectrum of needs Advanced diagnostic tools drive: Health impact for the individual patient Identifying the cause of illness to inform/guide treatment Selecting appropriate therapy for a patient Monitoring long term therapy to ensure efficacy and safety Health care system impact via population surveillance Identifying asymptomatic carriers Tracking the spread of disease and drug resistance Monitoring disease burden Tracking vaccination coverage and efficacy

TB Diagnostics overview and key strategic questions View from the field Need to develop tools that are appropriate in low-resource settings to detect disease and infection Robust, rapid, accurate, and low-cost Dx tools for both active and latent infection (latent infection important in HIV+ patients, diabetics)...and also to guide treatment selection: Robust, rapid, accurate, and low-cost test to detect MDR/XDR DST will be increasingly needed to determine adequacy of first line therapy if we move to shorter regimens BMGF Dx priorities Create competition, choice and a healthy diagnostics market 1. Discover biomarkers for active, pulmonary TB that can be used with novel PoC platforms 2. Expand adoption and range of uses for GeneXpert, e.g., broader drug susceptibility testing alternative energy sources operational certification at higher ambient temperatures pricing strategies for lowresource settings 3. Develop device strategy for low-cost, next generation alternative(s) to GeneXpert TPP guide for low-resource settings, e.g., lower-cost, fieldable at primary HC level or below Key questions What would accelerate Gene Xpert adoption given cost and infrastructure requirements? What is the 'right' performancefor-price profile for TB PoC Dx? How do we define 'POC' setting for TB, and what is the ideal TPP for each of these settings? How far do automated molecular devices (e.g., GeneXpert) go in addressing needs for underserved populations, i.e., HIV+, children, extrapulmonary TB, and where could nonsputum detection be transformative? How to balance investment in improved molecular diagnostics vs. new biomarker discovery?

This image cannot currently be displayed. Draft For discussion only GeneXpert price reduction and Fast Followers are steps in long-term path to point of care TB Dx Price ($) 33 30 27 GeneXpert 24 21 18 15 12 9 6 3 Smear + Culture GeneXpert price reduction 1st generation: Developed world Fast-Followers Next generation: Developing world PoC Dx / Biomarker Discovery Past 0-12 24-36 48-60 (?) 10-15 years+ Time (months) 2012 Bill & Melinda Gates Foundation 18

Evolving approach to foundation investments in diagnostics moving toward integration No integration Degree of platform integration Single test, single technology Past Present Most past investments have been on a disease by disease basis Future Multiple tests, single technology Recently we've begun to consolidate our investments Multiple tests, multiple technologies Panels of tests would inform local treatment decisions Full integration

Technology scale-up: feeding back delivery evidence to product development cycles early is important July 15, 2013 Discovery Vaccines Initiative Drugs Initiative Development Diagnostics Initiative Resource mobilization 1. GeneXpert implementation/scale up 2. Intro new drugs/regimens (link to new DST development) 3. New drugs 4. other: ICT TB-MAC, CPTR Modeling impact with feedback loop to product development Global Access and launch GFATM, WHO, STP, UNITAID TB programs in country GeneXpert Example: South Africa HIV-TB integration India ICT PPM China CDC/Hospital Brazil Replacement for smear WHO: normative UNITAID: mkt impact GFATM: scale up Countries: self-finance Impact Goal: accelerated reduction in TB incidence Rest of World Diffusion 20

Evidence pathway: Impact at scale-up will depend upon key in-country decisions and the generation of evidence Placement of test in health system The diagnostic algorithm use Replacement for smear? What is best combination of tools? Identifying the correct suspect with TB & link to care Avoid use of expensive tests Costs to patient and health system (lab and care) GXP - and TB - Determine affordability and willingness to pay Budget Impact Cost effectiveness In S Africa 15 of 100 TB suspects have TB by Xpert, and not all are linked to care GXP - and TB + GXP + and TB + (sens. 80%) July 15, 2013 21

Lessons learned and country evidence July 15, 2013 2011 Bill & Melinda Gates Foundation 22

Source: GLI website July 15, 2013 2011 Bill & Melinda Gates Foundation 23

GeneXpert as a pathfinder: Major learning for future efforts Case Study GeneXpert represents an imperfect technology that has nonetheless initiated a paradigm shift for TB diagnosis while still too complex and expensive, it is a reliable, rapid diagnostic that can be deployed more widely. A lack of coordinated launch planning slowed initial roll-out. A series of lessons have been learned. Key Lessons Learned 1. Political decisions can accelerate any launch 2. Robust launch plans with clear roles and responsibilities are needed 3. Delivery is local and technology must be adapted into health systems 4. Funding institutions can maximize access by combining resources 5. Implementation needs to be coordinated effectively 6. Measurement of coverage and impact is most critical to support effective rollout GeneXpert Experience South African Minister of Health made announcement on GeneXpert without a detailed plan for scale-up. Launch planning by PDP and WHO was inadequate and came too late: inadequate policy guidance & market access planning. Price too high despite FIND agreement Guidance too vague Initial focus was on accuracy assessments rather than operational research. Roadmap and coordination for implementation research should be integrated into launch planning. Through combining the efforts of USG, the Gates Foundation and UNITAID, the price was reduced from $17 to $10 per cartridge with an immediate impact on orders and uptake. WHO was not funded to coordinate the roll-out and coordinate implementation which resulted in sub-optimal roll-out. Either WHO needs to be funded to do this or another body tasked with this to manage it effectively. The initial focus was too heavy on surveillance for adoption rather than coverage and impact of the tool. July 15, 2013 2010 Bill & Melinda Gates Foundation 24 2011 Bill & Melinda Gates Foundation 24

Proposed revised value chain for new TB diagnostics Journal of Infect Dis 2012

Number modules/cartridges as of Q1 2013 Politics of uptake Diagnostics algorithm Role of data in uptake Machines anticipated or planned Proportion of valid test results on initial test (after second test if required) Increase in labconfirmed diagnosis Module failure rate within 1 year South Africa 3060/1.3M Paid for by MOF Political support from MOH GX to replace AFB smear Convince MOF to sustain investment 288 for 100% coverage by Q3 2013 India China Brazil MSF Experience 253/109,042 36/11,160 76/34,260 112/36,540 Paid for by USAID, WHO Political resistance from MOH GX for drug susceptibility testing in remote areas TBD 97% 93% (99.1%) Estimated 53% 125/1888 (6.6%) GFATM support for scale up GX to replace AFB smear Data are changing gov t mindset 900 by 2014 with Global Fund resources Paid for by BMGF, USAID Political support from MOH GX to replace AFB smear Convince MOH to invest 120 to cover high prev cities and areas (60% of TB cases) Paid for by MSF GX in addition to AFB smear as part of pilot MSF monitoring uptake and adjusting strategy 95% 93% 88% 50% 59% 41% 43% 10/108 (9.25%) 2/36 (6%) 6/60 (10%) 11/112 (9.8%) Mozam (rural) 52/29,560 Paid for by CIDA/WHO GX for AFB smear negative patients only 12/16 (75%) Key data from GeneXpert implementation (summarized from various sources as of July 2013) July 15, 2013 2011 Bill & Melinda Gates Foundation 26

Early lessons from a S. Africa PHC clinic Xpert arm Routine arm P-value Randomized (ITT) 1007 1144 Initiated TB treatment* 297 (29.5%) 276 (24.1%) P=0.005 Bacteriologically confirmed cases initiated on TB treatment Initiated on TB treatment without bacteriologic confirmation (% of cases initiating TB treatment) 226 (22.4%) 129 (11.3%) P<0.0001 70 (23.6%) 146 (52.9%) P<0.0001 Median time to treatment initiation 4 days 10 days P<0.0001 Started TB treatment 297 276 Successful TB treatment 240 (23.8%) 205 (17.9%) P=0.0007 Died within 6 months of sputum sample 37 (3.7%) 54 (4.7%) P=0.229 Source: Mark Nicol, manuscript in preparation, 2013: Impact of Xpert MTB/Rif implementation in a primary health care clinic in South Africa a pragmatic randomized trial July 15, 2013 2011 Bill & Melinda Gates Foundation 27

Public Sector Diagnostic Costs (costs may be underestimated) 20 Price USD 18 16 14 12 10 8 GX $16.86 GX $14.00 GX $10.70 Smear Culture DST 6 4 2 0 India China Brazil Indonesia Uganda South Africa* Median Notes: *South Africa Smear, culture prices from CDC/South Africa spreadsheet, DST from FIND DST = (2 drugs and culture except for Uganda and RSA which have 5 drug DST only Source: FIND. Diagnostics for Tuberculosis: global demand and market potential

Clinical impact of test results on diagnostic and treatment decisions, and eventually, patient outcomes Test results Change in physician s decisions Correct treatment choices Improved patient outcomes The value of diagnostic tests ultimately lies in their effect on patient outcomes Improved accuracy is not always a necessary prerequisite for improving patient health, nor does it guarantee other downstream improvements [di Ruffano et al. BMJ 2012;344:e686] M. Pai, Diagnostics Research Course, McGill Univ, July 2013

Brazil experience: physician behavior slower to change than adoption of new tool Xpert as replacement for smear in 2 large municipalities, Rio & Manaus Pragmatic trial: randomized, step-wedge design Primary outcome: confirmed TB diagnosis Economic analysis: Budget Impact Analysis, CEA including patient costs Findings: 59% increase in laboratory confirmed notifications But only a 16% increase in total notifications Delay to treatment initiation improved from 4 to 2 days (median) $14.40 USD for 2 smears vs 17.80 USD for 1 GeneXpert test Conclusions: labor costs are important drivers of overall cost and CE Physicians rapidly accepted Xpert results into algorithm but still treat many patients based on clinical diagnosis alone July 15, 2013 2011 Bill & Melinda Gates Foundation 30

Role of private sector: understanding provider incentives for providing international standards of care is another key element Test results Change in physician s decisions Correct treatment choices Improved patient outcomes M. Pai, Diagnostics Research Course, McGill Univ, July 2013

Operational systems matter and direct decision making for new diagnostics: simplified diagram of TB diagnostic & treatment processes Lin, et al. IJTLD 2011:996-1004 July 15, 2013 2011 Bill & Melinda Gates Foundation 32

Pantoja 2009, slide courtesy of C Dye, WHO Doctors and delays, Bangalore No. doctors seen by TB patients More doctors, longer treatment 180 160 Women 250 80 No. female patients 140 120 100 80 60 40 20 Men 200 150 100 50 No. male patients Total duration (days) 60 40 20 Each extra doctor seen adds 12 days 0 1 2 3 4 5 6 7 Number of doctors 0 0 0 1 2 3 4 5 6 7 8 Number of doctors

Understanding the role of the private sector relative to public government services: India example Kapoor SK et al. PLoS ONE 2012 Union Midline KAP Survey just completed Incentives study by JPAL (evaluation of Op Asha) July 15, 2013 2013 Bill & Melinda Gates Foundation 34

Private Sector Diagnostic (smear and culture, costs may be overestimated) 20 18 16 GX $16.86 14 GX $14.00 Price USD 12 10 8 Smear Culture GX $10.70 6 4 2 0 India China Brazil Indonesia Uganda South Africa Median Notes: *South Africa Smear, culture prices from CDC/South Africa spreadsheet Source: FIND. Diagnostics for Tuberculosis: global demand and market potential

Much higher retail prices in Indian private sector found by other research 120 100 $100 80 Price USD 60 Min Max 40 20 0 $3 $5 $15 Smear Liquid Culture Liquid Culture + DST $30 GX $16.86 GX $14.00 GX $10.70 Source: Madhu Pai re: survey of high class urban labs in India

Impact assessment should help revise policies through rapid feedback loops: a role for modeling Cobelens F, van den Hof S, Pai M et al. Journal of Infect Dis 2012

Modelling to inform TB control in S. Africa Rapid scale up of combination TB prevention will be critical, but are the targets achievable? (Source: C. Dye et al, 2012) South Africa won t reach its targets using existing tools, but what components of South Africa s NSP will have the largest impact? (Source: R White et al, 2013) Cases (million/yr) 0.5 0.4 0.3 0.2 0.1 Combining interventions to control TB in South Africa 0.0 1990 2000 2010 2020 2030 2040 2050 adding interventions ART HIV+ diagnosis detection cure TLTI HIV+ TLTI HIVpre-exp vaccine residual Reduction in TB incidence Reduction in TB incidence 50% 40% 30% 20% 10% 0% 100% 80% 60% 40% 20% 0% 2016 (50% reduction) ART to IPT (6m) cure ART to initial TB+HIV+ to PLHIV CD4<350 default A. case finding 2032 (~elimination) ART to IPT (6m) cure ART to initial A. case TB+HIV+ to PLHIV CD4<350 default finding All (NSP) All (NSP) << Target << Target TB MAC is fostering collaboration between TB modellers and policy makers to review national TB program targets and prioritization of interventions in South Africa 2011 Bill & Melinda Gates Foundation 38

Using evidence to shape policy and implementation Modeling for Delivery The What Decision analysis Economic modeling Cost-effectiveness modeling Transmission modeling Operational/HS modeling To answer targeted questions for programs and our strategy What is the impact of TB drugs, dx & vaccines on incidence? What is the CE of Xpert, other tools? Why didn t CREATE work? How to incentivize the private sector to deliver quality care Outcomes Program targets developed Policy changed Financing secured Operational decisions made re: prioritization of interventions Feedback to future TPPs The How http://tb-mac.org TB MAC was formed in 2012 to bring together multiple disparate TB modeling efforts and coordinate them to support outcome driven modeling for delivery. 2011 Bill & Melinda Gates Foundation 39 3 9

Conclusions on data needs for scaling up for impact Placement of test in health system The diagnostic algorithm use Replacement for smear? What is best combination of tool? Identifying the correct suspect with TB & link to care Avoid use of expensive tests Costs to patient and health system (lab and care) Determine affordability and willingness to pay Budget Impact Cost effectiveness 1. There is an accelerating paradigm shift in diagnostics : we need to get smarter and faster in optimizing the intertwined value chains 2. Still learning about in-country processes & required levels of evidence 3. Feedback loops to both policy makers and product developers are critical components of the future July 15, 2013 40