Speaker: Jim Gallarda, Bill & Melinda Gates Foundation
Jim Gallarda set the stage for the day by considering how success in improved diagnostics should be defined, and stressing the need for innovation from both the supply (developers) side and the demand (users, uptake, and implementers) side. Gallarda emphasized that incentives are needed on all sides for successful innovation, noting that each player in the chain from developer to patient has different priorities, incentives, and definitions of success.
Diagnostic Manufacturing in Low- and Middle-Income Counties (LMIC): Criteria Used to Decide Country Partnerships and In-Country Perspectives
Speaker: Dan Laser, Wave80 Biosciences
Dan Laser reminded the participants that in local markets, key factors such as disease burden, technical capacity and capabilities, and investment level (either local or by donor) are among standard criteria for launch planning. When considering the issue of manufacturing, additional metrics such as strength of local distribution network and potential advantages of local production come into play as well. Laser’s presentation discussed the balance of motivating factors and practical considerations surrounding LMIC manufacturing of products.
Speaker: Palu Dhanani, Universal Corp Ltd
Complementing the previous address, Palu Dhanani offered perspective from a local, WHO-prequalified manufacturer on the desire to and benefits of being an important player in supply of new technologies. Specific dynamics covered included the benefits to availability from local supply, as well as the notion that larger manufacturers often face challenges when dealing with smaller orders.
Keynote Addression Question and Answer Session
Beyond Diagnostic Accuracy: Improving TB Health Outcomes
Speaker: Claudia Denkinger, FIND
In the spirit of the Workshop’s theme of innovation meeting implementation, Claudia Denkinger set the stage for this session by reminding the audience of the need to think beyond just scientific innovation to impact all areas from development all the way through access.
The Need to Expand Scope: Life Beyond Probes
Speaker: Jim Gallarda (BMGF)
Echoing an emerging theme, Jim Gallarda emphasized the concept of “end to end thinking,” to influence decision-making criteria along the development path and forge an evolved set of dynamics on the implementation front. Gallarda broke down how a patient or health care worker might experience treatment, and the need to consider those realities to develop a holistic view of innovation and need. Anticipating such needs will accelerate the pace of innovation and impact.
The Diagnostic Landscape: Translation Challenges
Speaker: Madhukar Pai: McGill University
Madhukar Pai focused on downstream challenges. While the pipeline of new products continues to go grow, reaching patients remains a challenge. Pai outlined “TB Care Cascades” to show how patients are lost in various points throughout the process of seeking care, and highlighted that reducing gaps and accelerating the process will be key to improving outcomes – with current or new technologies. Process innovation must accompany product innovation.
Target Product Profile (TPP) and Changing Needs
Speaker: Claudia Denkinger, FIND
Claudia Denkinger began her presentation by summarizing the processes conducted to reach the TB diagnostic TPP that was published in 2014. Denkinger then raised questions about the changing treatment and development landscape, remarking that diagnostic developers must also stay atop of the current state of drug research in order to adapt and revise the priorities of the patient population. She laid out future needs and areas of improvement within the field.
Personal Next Generation Sequencing Devices to Meet Universal Drug Susceptibility Testing Needs
Speaker: Michael Metzker, RedVault Biosciences
Michael Metzker noted that next generation sequencing has dominated the DST field over the past decade, but conceded that the technology can’t do it all. Metzker discussed technologies in development or that have been implemented in other disease areas and how they may be adaptable or generate lessons relevant to TB.
Overview of Technological Platforms
Several diagnostic product developers provided brief updates on technologies in various stages of development, and strategic choices made regarding what products to pursue and what technological platforms and specs were chosen. Participants included:
A lively and thorough panel discussion, led by Madhukar Pai, followed the session.
Molecular Basis for Drug Resistance Versus Susceptibility: Assay Design Implications
Speaker: Barry Kreiswerth, Public Health Research Institute, Rutgers University
Barry Kreiswerth opened this session by noting that it will have a molecular focus. Kreiswerth referenced the history of genome sequencing and some of the learnings it generated regarding M.tb. He then noted that some TB drugs – particularly, pyrazinamide – don’t seem to follow traditional patterns, leading to a need for substantial study, given its role in TB therapy.
Resistance to Pyrazinamide: Defining pncA Mutations
Speaker: Jamie Posey, CDC
Pyrazinamide has shown it plays an important role in treatment-shortening with TB therapy regimens. Resistance to the drug is on the rise, however. Jamie Posey presented data on mutations that can cause resistance and discussed how resistance to the drug is defined. Posey discussed improving the accuracy of pyrazinamide DST in the MGIT platform and provided data from a robust study to offering a path toward progress.
Lights On/Off Clinical Evaluation in South Africa
Speaker: Rob Warren, Stellenbosch University
Rob Warren set the stage for his discussion by explaining the current state of MDR-TB in South Africa and the existing DST strategy within the country. Warren went on to detail the Lights On/Off methodology, which uses fluorescence to detect resistance. He explained the processes as it relates to detecting fluoroquinolone and pyrazinamide resistance.
Novel Mutations Associated with Clofazimine Resistance
Speaker: Ying Zhang, Johns Hopkins University
Clofazimine shows promise for shortening the treatment of both TB and MDR-TB, especially when combined with other TB drugs. Its mode of action is complicated however, and its target remains unknown. Ying Zhang presented on mutations and mechanisms of resistance to clofazimine, as well on data relating to cross-resistance. However, additional research is needed to better understand the workings of the drug and to develop improved means of DST for clofazimine.
Sequencing Sputum for Rapid Drug Susceptibility Testing
Speaker: Dave Engelthaler
Dave Engelthaler presented on Targeted Amplicon Sequencing, which combines the sensitivity of PCR with the Information Power of sequencing and can be done straight from sputum. Engelthaler shared data from reports run with the technology and discussed the possibility of being able to detect “pre-resistance” – predicting resistance before it actually occurs.
Multi-Drug Resistant Strain Transmission and Evolution: Implications for Treatment and Assay Development
Speaker: Stefan Niemann, National Reference Center for Mycobacteria
Stefan Niemann discussed concepts of resistance development and the implications of how the dynamics of transmission and resistance evolution impact one another to help color the global MDR-TB landscape. Niemann illustrated this by presenting a case study of resistance in Swaziland, showing that the bottleneck of MDR-TB treatment heads to the selection of few MDR-TB outbreak variants. He highlighted the need for additional research to further define and trace these dynamics.
Speaker: Marco Schito, Critical Path Institute
Marco Schito wrapped the day’s proceedings by reflecting on the progress made in the DST area and on the scope of work covered throughout the day. Schito stressed the importance of having a wide array of developers involved in this work and the value of collaboration.