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Title:

Diagnosing Infection at the Point of Care

Image of Report Cover: Diagnosing Infection at the Point of Care
Authors:
Jennifer B. Nuzzo, Kunal Rambhia, Ryan C. Morhard, Matthew Watson, Amesh Adalja, Eric Toner, Anita J. Cicero, Thomas V. Inglesby
Date posted:
June 03, 2013
Publication type:
Report
Publication:

UPMC Center for Health Security, June 3, 2013 

Publisher:
The Point of Care Diagnostics project was supported by DTRA Chem Bio Directorate under contract #HDTRA1-11-D-0004.
Availability:
Open access
See also:
Introduction:

Diagnostic tests are critical for diagnosing diseases in US troops, for domestic and in­ternational early disease detection and bio­surveillance, and for improving global health.1 Advances in diagnostics could improve clinical management of a range of diseases in the US healthcare system. The ability to rapidly di­agnose infectious disease has been identified as a strategic priority by the White House,2,3 the US Department of Health and Human Ser­vices (HHS),4 the National Institutes of Health (NIH),5 the US Centers for Disease Control and Prevention (CDC),6 and the US Department of Defense (DoD).7


Executive Summary

Diagnostic tests are critical for diagnosing diseases in US troops, for domestic and in­ternational early disease detection and bio­surveillance, and for improving global health.1 Advances in diagnostics could improve clinical management of a range of diseases in the US healthcare system. The ability to rapidly di­agnose infectious disease has been identified as a strategic priority by the White House,2,3 the US Department of Health and Human Ser­vices (HHS),4 the National Institutes of Health (NIH),5 the US Centers for Disease Control and Prevention (CDC),6 and the US Department of Defense (DoD).7

One category of diagnostic technologies—rap­id point-of-care (POC) tests—offers a number of possible advantages over other diagnostic approaches. POC diagnostics have the poten­tial to expedite clinical decision making, to reduce patient loss to follow up while waiting for test results, and to facilitate the delivery of care outside traditional healthcare settings. POC diagnostics also are appealing for use in lower cost environments because they require less complex infrastructure and training.

While the overall global diagnostics market is projected to surpass $50 billion in 2014, POC tests represent only a small portion of that market: 12% of the total ($5.5 billion). In addi­tion, infectious disease diagnostics represent a small slice of the overall global diagnostic market and the POC market.8 Currently, the number of infectious disease POC tests that are approved for use in the United States is limited and focuses on a small set of com­mon clinical conditions. Tests cleared by the Food and Drug Administration (FDA) exist only for HIV, HCV, influenza, RSV, EBV, Group A Streptococcus, adenovirus, Helicobacter pylori, trichomoniasis, bacterial vaginosis, and Borrelia burgdorferi(although cleared by the FDA, the POC test for Lyme disease does not currently appear to be commercially available).9 There are no POC tests available for less common but high consequence diseases of concern, including biothreat agents.

There is increasing interest in exploring ways to accelerate the development of new rap­id POC diagnostics. The Grand Challenge in Global Health Diagnostics10 was launched in 2011 by the Bill and Melinda Gates Foundation and Grand Challenges Canada to catalyze the development of a common, open-source plat­form that could be used to diagnose multiple pathogens at the point of care.11 Developing and using standards to facilitate diagnostic development has been proposed as part of this effort.12 In addition, the Defense Threat Reduction Agency (DTRA) is sponsoring the 24-Month Challenge to develop POC diagnos­tics suitable for both mobile and clinic-based applications.13

This report examines the clinical needs, busi­ness case, and challenges facing today’s POC infectious disease diagnostics market, and it considers what role standards and other ap­proaches may play in catalyzing the develop­ment of new POC diagnostic tests.

Purpose of Project: The UPMC Center for Health Security (formerly the Center for Bi­osecurity of UPMC) conducted this project to provide leaders in DoD, other agencies of the US government, and nongovernmental organi­zations (NGOs) engaged in global health pro­grams with an assessment of possible strate­gies and initiatives that could be employed to speed the development of rapid diagnos­tic tests that would detect, identify, and help inform the treatment of infectious diseases. This project included a focus on the potential development and use of standards for infec­tious disease diagnostics, as well as on barri­ers, challenges, and opportunities related to the development and uptake of new diagnos­tic tests, particularly those at the point of care.

Methodology: To inform this analysis, Cen­ter staff conducted a review of the published literature relating to point-of-care infectious disease diagnostics, key policy analyses, and government and nongovernment reports on current technological approaches. The Center held more than 40 conversations with lead­ers and subject matter experts responsible for infectious disease diagnostic research, devel­opment, policy, or practice. Based on those conversations, the Center prepared a prelimi­nary analysis of our findings. Finally, the Center convened a 1-day meeting on January 29, 2013, that was attended by members of industry, ac­ademia, nongovernmental organizations, and the government, in which the preliminary anal­ysis was presented and discussed by partici­pants. This report identifies major findings and recommendations emerging from the Center’s analysis, the interviews, and workshop discus­sions. The conversations before the workshop and discussions on January 29 were conduct­ed on a not-for-attribution basis. The recom­mendations represent the views of the Center and may or may not represent the views of any of the project participants.

Findings

1. In the right settings, standards can be used to accelerate emerging technology development.

When applied with the proper scope and at the proper time, standards can help realize desired technical, economic, and/or policy objectives, including technology development and diffusion. Standards can contribute positively to innovation by facilitating cooperation between organizations; increasing product performance, homogeneity, and interoperability; accelerating the diffusion of technical solutions; and improving regulation by enabling comparability, conformity, and predictability.

2. When applied too early in the technology development process, standards may contribute to institutionalizing inefficient practices and stifling innovation.

Standards have the potential to limit innovation by promoting the adoption of inferior products, even in the presence of more technologically advanced or more desirable alternatives. The timing of the development and application of standards is highly consequential. One serious concern is that standards can create “lock-in” effects and make the diffusion of more efficient innovations more difficult due to high switching costs.

Some notions of future diagnostic technologies are that platforms will (or should) require compat­ible, and perhaps proprietary, components, such as cartridges. If such platforms were to gain influence in the market, new technologies may be required to be interoperable within these new technology ecosystems in order to be successful. This kind of networking effect in diagnostic technology de­velopment would cut both ways. Network effects enabled by standards might lead to increased technological development, but may also limit commercially viable, but diverse, avenues of in­novation.

3. Advances in diagnostic technology seem more likely to result from the collective application of standards by private companies with common proprietary goals than from the use of standards to create open platforms.

As standards are considered for diagnostic tech­nology, lessons from the computer revolution suggest that, rather than applying standards early in technology development to create open platforms, standards are most effective when adopted voluntarily by the private sector when it sees clear benefit and at a time of appropriate technology maturity.

Although it might seem logical that “open” platforms would lead to increased access and development of new technologies, as compared to closed platform technologies that are sold for profit, there is not a lot of evidence from the com­puter industry to support that notion. Ultimately, development and maintenance of advanced tech­nologies are best performed in the private sector, driven by competition for commercial success be­tween proprietary technologies and supplemented by the strategic application of standards to solve common problems.

4. There are a number of distinct categories of standards that could be adopted for diagnostic technologies, each category with different purposes and limitations.          

In order to understand the value and potential drawbacks to standards, it is important to be specific about which types of standards are under consideration. There are at least 5 major categories of stan­dards that are worth distinguishing and examining:

  • Performance standards define the desired results that a test should be able to provide, such as the test’s sensitivity, specificity, limits of detection, cost, and time to result.

  • User interface standards define product designs to control how the end-user interacts with the instrument to limit potential for user error and/or reduce device complexity.

  • Interoperability standards define the design of testing platforms and/or consumables to facilitate development of “plug-and-play” devices. There are 2 possible approaches to developing interoperability standards:

    • Interoperability standards can define a specific testing platform in a way that allows manufacturers to develop a variety of testing consumables for the device; or

    • Interoperability standards can define the testing consumables in a way that allows manufacturers to design platforms that are built to enable use of standard consumables.

  • Regulatory standards would increase the supply of quality-assured diagnostic products by developing standards that could improve the global regulatory environment.

  • Analytic standards define standardized materials, protocols, or methodologies for the development or evaluation of a new diagnostic technology.

5. The potential for standards to encourage the development of new diagnostic technologies will depend on companies’ willingness to embrace them.

The effect that a particular standard will have on the innovation and adoption of POC diagnostics will depend on how the standard is developed and whether it is embraced by developers. A company’s willingness to embrace a new diagnostic standard will depend on whether it supports that company’s business strategy.

6. There would be high value in creating standard specimen banks to facilitate diagnostics development.

Despite the existence of several culture or sample collections, the lack of availability of clinical or microbiological samples necessary for diagnostic research and testing is a significant barrier to in­novation and development. There is a need to de­velop standard samples and reagents to aid in the early development of new diagnostic technologies. Sample banks would be useful in the performance of validation testing of diagnostics for regulatory clearance evaluations. Emphasis would be placed on ensuring that, for a bank to be of high value, it would need to contain a sufficient variety of strains and would need to have samples that are highly pedigreed.

7. New diagnostics need to improve clinical decision making in order to be broadly adopted.

The clinical community is the primary end-user of infectious disease diagnostics in the developed and developing worlds. The needs of clinicians and the decisions they make drive the use of diagnos­tics tests. Clinicians are not likely to use a diagnos­tic test if the results will not change the treatment or if there is no important clinical decision that depends on the result of that test.

Adoption of new tests by the clinical community takes time, because clinical practice patterns are difficult to change. Many diagnoses are made on clinical grounds based on a clinical history and a physical examination. Clinicians are taught that di­agnostic tests should be used to rule in or rule out a clinical diagnosis if using such a test would make a difference that is “clinically relevant.”

8. Diagnostic standards should be flexible enough to accommodate changing user needs, such as the potential increased demand for in-home POC testing.

As POC diagnostic technologies mature and be­come more widely used, the potential exists for use strategies or trends to differ from the status quo, including the possibility of increased use of diagnostics in the home. Existing or new diagnos­tic standards may need to be reevaluated depend­ing on how these use trends evolve.

9. Commercial market challenges will continue to hinder the development of in vitro diagnostics.

Currently, market forces create disincentives for the development of new POC infectious disease diagnostic tests. Many technical and regulatory challenges exist that will have to be overcome before firms will commit resources to the research and development of diagnostic tests for use at the point of care. Tests must be CLIA (Clinical Laboratory Improvement Amendments) waived to be used at the point of care, and CLIA waiver is perceived by developers to be a significant hurdle. Non-POC tests may offer a more profitable ap­proach to diagnostics development. All of these factors are relevant in considering whether a sus­tainable business model can be implemented for infectious disease POC diagnostics.

Recommendations

1. Define which POC diagnostic tests are most important for US government and NGO needs.

It would be valuable if DoD, other US government agencies, and nongovernmental organizations that are focused on diagnostics development for infectious diseases established a list of top diagnostic development priorities or require­ments. The US government might consider sponsoring an ongoing process that includes DoD, the Biomedical Advanced Research and Development Authority (BARDA), CDC, FDA, the Gates Foundation and other entities, including clinicians, with an interest in developing POC and laboratory-based diagnostic tests for infectious diseases. This process should identify specific disease diagnostic priorities, desired characteristics of each diagnostic test on the requirement list, and a concept of use for each diagnostic test requirement.

2. Distinguish the settings and infections for which POC diagnostic tests should be the priority versus those for which in-laboratory tests would be of greater value.

Although POC diagnostics can offer a number of advantages over in-lab testing, they should not be the only approach that the US government supports. Only a limited suite of technologies have achieved CLIA waiver or are likely to do so. Therefore, the US government should consider whether testing diseases in a CLIA-approved labo­ratory will be sufficient or even advantageous. As the US government considers which diagnostic testing priorities it will support, it should also indicate which of those priorities are better pursued with POC strategies versus those that are better pursued by moderately complex or highly complex in-lab tests.

3. Consult with industry and NGOs to develop analytic standards, such as clinical sample banks.

The US government should identify those clinical specimens and reagents that are most needed for research, development, and evaluation of prior­ity diagnostic technologies and establish a process for storing, managing, and financing a bank of those analytic standards. This work should build on existing efforts at CDC, the National Institute of Standards and Technology (NIST), and elsewhere.
 

4. Bring together industry and a standards-setting organization to explore specific applications of standards to diagnostics.

The US government should convene key industry stakeholders, along with a standards-setting organization, to collectively identify technical obstacles that are commonly being encountered that might best be solved by standards. A stan­dards-setting organization (eg, the Clinical and Laboratory Standards Institute, or CLSI) dedicated to facilitating dialogue across industry could help articulate specific industry needs that might be best addressed by the focused application of standards. In addition to helping to identify opportunities for standardization, a standard-set­ting organization like CLSI could engage with a new or existing industry consortium to assist in the implementation of the agreed-upon standards.
 

5. The US government and other organizations wishing to encourage the development of POC infectious disease diagnostics will have to directly assist in the creation of a market for the desired products.

To ensure the availability of needed POC tests, the US government should coordinate with relevant stakeholders to ensure the existence of a viable market. While it remains unclear which procurement model will predominate for POC di­agnostic tests, issues regarding reimbursement and cost will continue to be decisive factors in the development and diffusion of these technologies. Selecting the most appropriate pur­chasing mechanism will require an analysis of local market dynamics, whether in the devel­oped or developing world. Regardless of use setting, however, diagnostic test manufacturers will have to be convinced of the viability of the market demand for their product in order for them to invest in research, development, and manufacturing capacity. As the US government and other organizations consider whether and how to facilitate the development of diagnostic standards and new diagnostics tests, they will also need to consider how to create and sustain a market for these vitally important products.

References

  1. Nuzzo JB, Rambhia KJ, Wollner SB, et al. Diagnostics for Global Biosurveillance: Turning Promising Science into the Tools Needed in the Field. July 2011; http://www.centerforhealthsecurity.org/our-work/pubs_archive/pubs-pdfs/2011/2011-09-13-global-biosurveillance-DTRA.pdf.

  2. The White House. National Strategy for Biosurveillance. 2012; https://obamawhitehouse.archives.gov/sites/default/files/National_Strategy_for_Biosurveillance_July_2012.pdf. Accessed February 11, 2013.

  3. National Security Council. National Strategy for Countering Biological Threats. 2009; December 9, 2009 Available at: https://obamawhitehouse.archives.gov/sites/default/files/National_Strategy_for_Countering_BioThreats.pdf. Accessed February 11, 2013.

  4. Department of Health and Human Services. National Health Security Strategy of the United States of America. 2009; December 7, 2011 Available at: https://www.phe.gov/Preparedness/planning/authority/nhss/Documents/nhss0912.pdf. Accessed February 11, 2013.

  5. Korte B. Point-of-Care Diagnostic Testing. 2010; http://report.nih.gov/nihfactsheets/Pdfs/PointofCareDiagnosticTesting(NIBIB).pdf.

  6. Centers for Disease Control and Prevention. Report to Congress on Internal Laboratory Activites of CDC and Associated Funding Levels May 2012; http://www.cdc.gov/osels/lspppo/pdf/LSPPPO_Report_Signed_V2%20(clear%20version).pdf. Accessed February 11, 2013.

  7. Defense Threat Reduction Agency. Chemical and Biological Defense. http://www.dtra.mil/Missions/ChemicalBiologicalDefense/ChemicalBiologicalDefenseHome.aspx. Accessed February 11, 2013

  8. Witonsky J. IVD Market Moving Rapidly on an Upward Trajectory. 2012; http://www.genengnews.com/gen-articles/ivd-market-moving-rapidly-on-an-upward-trajectory/4620/. Accessed February 13, 2013.

  9. Dekker JP. Infectious Disease Testing at the Point-of-Care. Point of Care. 2012;11(2):85-89.

  10. Bill and Melinda Gates Foundation. Gates Foundation and Grand Challenges Canada Announce over $31 Million for Point-of-Care Diagnostics in the Developing World. December 2011; http://www.grandchallenges.org/about/Newsroom/Pages/POC_DxGrants.aspx. Accessed February 11, 2013.

  11. Bill and Melinda Gates Foundation. Grand Challenges in Global Health Diagnostics. 2011; http://www.grandchallenges.org/GCGHDocs/GCGH_Dx_Public_RFP.pdf. Accessed February 11, 2013.

  12. Walther G. Enabling POC Diagnostics through Standard Setting. Paper presented at: World Health Summit; 21 October, 2012; Berlin, Germany.

  13. Defense Threat Reduction Agency. DTRA Point of Care Diagnostics for Multiplexed Targets. 2012; https://www.fbo.gov/index?s=opportunity&mode=form&id=eb0d8db0d46f190ee282a8e70b7ef768&tab=core&_cview=1.

 

 

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