An open-source molecular diagnostic platform approach for outbreak and epidemic preparedness

Background Diagnostic development for outbreak pathogens has typically followed a disease-specific reactive rather than proactive response. Given the diversity of outbreak pathogens, particularly those prioritised by the World Health Organization Research and Development Blueprint, a more flexible and proactive approach to epidemic preparedness is needed to expand access to critical molecular diagnostic tests in peripheral and resource-constrained deployment settings. Objective New and more sustainable directives are needed to spur the development of high-quality products, particularly for epidemics more often found in low- and middle-income countries. To leverage and de-risk the development process, we present the benefits and challenges of an open-source business model for co-development of molecular diagnostic tests for decentralised settings. Methods We identify key outbreak pathogens that are available only for testing in high infrastructure laboratories and compare in-country installed base platforms that could be leveraged for menu expansion. Key strengths and challenges for development are highlighted for both platform and assay developers, with discussion of how to leverage and de-risk the process through an open-source development model. Results Depending on the specific partner strengths, options for partnership roles are presented. The proposed open-source business model addresses the particular challenges in the detection of outbreak- and epidemic-prone pathogens in low- and middle-income countries, reduces development and deployment risks to support outbreak response, strengthens diagnostic capacity and creates a viable market for product developers. Conclusion We hope this model for a collaborative and open-source approach for molecular diagnostics serves to encourage stakeholders to consider co-development partnerships to improve outbreak preparedness and epidemic/pandemic response.


Introduction
Diagnostics are a fundamental component of a successful outbreak response by enabling surveillance and early detection, rapid and appropriate patient management, and objective evaluation of outbreak containment, in addition to facilitating therapeutic and vaccine development. 1,2,3,4 For outbreak and epidemic-prone pathogens, diagnostic development has typically followed a disease-specific reactive approach. Faced with significant mortality and morbidity during the 2013-2016 Ebola virus disease and 2015-2017 Zika virus epidemics, substantial global funding was made available, resulting in the rapid development of new diagnostics, therapeutics and vaccines. 5,6,7,8 However, only a handful of the diagnostic tests survived to become commercial products, and few found a sustainable market once the epidemics were declared contained and public funding was diverted elsewhere. 5,9,10 similar clinical symptoms (e.g. Lassa fever and Ebola virus disease, Middle East Respiratory Syndrome coronavirus and influenza), an additional challenge for rapid and definitive diagnosis. 2,14 Rapid pathogen identification can be critical when early detection can direct lifesaving treatment and intervention, such as antibiotics for confirmed bacterial infections 15 or vector control vaccination campaigns during a yellow fever outbreak. 2 There are common challenges to the deployment of diagnostic tests during outbreaks. 16 Early detection and contact tracing at the first stages of an outbreak are critical to rapid containment. Similarly, a rapid test turn-around time enables patients to be triaged both quickly and appropriately. In settings of endemic diseases with similar clinical indications, it will be invaluable to rapidly differentiate and identify the pathogen responsible for the outbreak. This kind of dynamic outbreak response demands access to diagnostics across a wide range of infrastructure, from reference laboratories to near-patient (NPT) hospital laboratories to point-of-care (POC) clinics and community testing.
In particular, the priority pathogens identified by the World Health Organization Research and Development Blueprint 17 present a challenge for diagnostic development for epidemic preparedness by any single developer, as the pathogens cover a wide range in clinical presentation, transmission mode, specimen type, lineage diversity, geography and outbreak frequency. A more flexible approach is needed to rapidly develop or adapt diagnostic tests for a wide variety of pathogens, which can be implemented in outbreak-appropriate deployment settings. 18,19,20 Molecular diagnostics for epidemic preparedness Molecular diagnostics (MDx) plays an important role in disease diagnosis (detection and confirmation of active infection), case management and surveillance, as well as a supporting role in therapeutic and vaccine trials. Due to the processing complexity and risks of contamination, MDx testing capacity is traditionally available only at reference-level or high-resourced laboratories, which can significantly delay patient diagnosis and intervention during an outbreak when specimen transport is a challenge. Molecular diagnostics testing is particularly useful at peripheral health facilities, where sick patients first present, to allow for pathogen detection. However, peripheral settings typically have limited resources for laboratory testing: NPT settings describe hospital and clinicassociated laboratories or mobile units, which support a minimal level of laboratory infrastructure and personnel; POC settings typically lack any laboratory infrastructure, including bedside, primary care and communitybased testing. 21 Near-patient/point-of-care MDx platforms have been designed specifically to meet the requirements for rapid pathogen detection in low-infrastructure settings, 22,23,24,25,26 with a compact and automated design for a simplified 'sample in, result out' processing. 18,19,27,28 Near-patient/ point-of-care MDx target product profiles have been described in detail. 29,30,31,32 Successful implementation has been demonstrated in decentralised laboratories in LMICs for diseases including HIV, tuberculosis, Zika virus, Ebola virus disease and influenza, 22,23,24,33,34,35,36 suggesting that a broader menu of assays could be developed for these NPT/POC platforms for outbreak detection. Table 1 presents a list of outbreak pathogens identified as high priority pathogens for medical countermeasures due to their high epidemic and pandemic potential. 37,38,39 Most of these diseases have MDx tests (reagent kits) that are commercially available, but appropriate only for use in high infrastructure research laboratories. In some cases, the MDx test has not been validated clinically or approved for diagnostic use (i.e. research-use-only kit), while in other cases, particularly for newer pathogens, MDx tests are available only as published protocols from trusted reference laboratories. 17,38,40 There is potential for available laboratory kits to be re-engineered for NPT/POC testing, including kits for viral haemorrhagic pathogens 41,42,43,44 , arboviral diseases, 45

Open-source diagnostic model
In LMIC settings, leveraging the existing diagnostic infrastructure is key to expanding the capacity for disease management and outbreak preparedness. Rather than requiring repeated de novo investment, existing platforms could be utilised for test menu expansion, building on the existing human resources, laboratory testing capacity and supply chains. A similar approach has seen success in the integration of tuberculosis-and HIV-testing at peripheral health centres. 57  This open-source model is intended to catalyse a more rapid approach to the development of diagnostic tests for decentralised or low-infrastructure settings, and to provide a more flexible approach to manufacturing tests for novel and endemic pathogens for LMICs through codevelopment (Table 3). Variations on the co-development partnership include collaborative research, test kit sub-contract manufacturing, and licensing or acquisition. These variations each require specific research and development and supply agreements, as well as marketing and product support agreements between the partners. In some cases, a highly successful development partnership could lead to downstream acquisition. Even in cases with limited sales, the ability to rapidly develop and deploy NPT/POC tests for novel pathogens is valuable in improving local outbreak response.

Model benefits and challenges
An open-source model for diagnostics can provide a more flexible and cost-effective approach to MDx deployment in peripheral settings, provided that commercial developers can find mutual benefit in a strategic partnership rather than traditional competition. The co-development model outlined above is intended to leverage the differential strengths between assay and platform developers by By leveraging existing assays and NPT/POC infrastructure, new tests can be rapidly re-engineered with a more cost-effective and 'on demand' approach for manufacturing. For the platform developer, a comprehensive assay menu expands the user base, which may provide more resilient and sustainable market volumes for diagnostic manufacturing.
For the assay developer, their existing assay portfolio is expanded to include testing across a broad range of settings. 58,59,60,61 Designed to utilise existing LMIC resources, an acknowledged potential disadvantage of this business model is reduced competition in favour of entrenched player market stability and product availability. Novel molecular platforms must be evaluated, both for their potential implementation in LMICs, as well as their openness to work with partners in developing assays, particularly for outbreakprone diseases.
To support this new development model, innovative partnerships and finance solutions are needed, especially for proactive development and commercial viability.
Here, the role of product development partners can serve as both matchmaker and co-investor to incentivise co-development partnerships. 62 The open-source model is currently being piloted by the Foundation for Innovative and New Diagnostics to partner diagnostic assay and platform developers in support of outbreak preparedness in the near term (2-5 years). 58 Similarly, this development model would also benefit from support from the global health community toward sustainable market commitments, pooled procurement mechanisms, and funding for test stockpiling to establish more sustainable supply chains and support long term commitments to diagnostic manufacturers. 16 Some of these mechanisms are in place to address similar challenges in the vaccines sector and should be explored and adapted for diagnostics. 63

Conclusion
Despite the influx of interest at the onset of a new outbreak, it is more often the case that research and development costs for new diagnostics may be too high relative to market size to provide a sufficient incentive for product development, and sustained support can be particularly challenging, for pathogens that present seasonal or sporadic markets. Alternative business models for diagnostic development could help reduce the high costs associated with bringing a new pathogen test to market. An open-source development partnership model can combine the strengths of commercial developers to reduce development the cost and time to market, while supporting existing supply chain infrastructure, training and proficiency. 29,32 Certainly, there are additional upstream and downstream challenges for pathogen test development. For new or poorly understood outbreaks, there are uncertainties in pathogen identification, epidemiology and disease kinetics. Newly developed tests require additional resources for clinical validation, for which well-characterised specimens and calibration standards may be difficult to obtain. 16 Commercial products also require international and/or in-country regulatory approval, though this may be a lower hurdle for assays that were previously validated as laboratory tests. Here, Product Development Partnerships can also serve as matchmakers to allow for sample sharing between research sites and developers with promising technologies, as well as to leverage in-country experience to support evaluation studies in LMICs that meet the requirements for regulatory approval.
The availability of appropriate diagnostics is a key feature for outbreak and epidemic preparedness. Early diagnosis of patients at initial point-of-care will enable timely patient and population interventions and support national surveillance systems for emerging and re-emerging diseases. Collaborative efforts are needed to develop NPT/POC diagnostics for all World Health Organization priority pathogens, to ensure access to high-quality diagnostics where testing is needed and to enable innovative funding mechanisms to support proactive development and market sustainability. We hope this article serves to encourage all diagnostic stakeholders (industry, academia, non-for-profit, non-governmental-organisations, governments) to foster partnerships in development and consider the open-source model early in the development of new diagnostics. Product support Platform developer provides all instrument and assay support for menu portfolio. Platform developer supports instrumentation and supply chain. Supply agreement between platform developer and assay developer.
Assay developer supports assay and supply chain. Supply agreement between platform developer and assay developer.

Marketing and deployment options
Assay developer provides contract research with licensing agreement to platform developer. Assay developer is OEM source for cartridge-ready reagent kits. Assay developer is independent source for reagent kits and cartridges, supply and co-marketing agreement with platform developer.
OEM, original equipment manufacturer.