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Diagnostics for Global Biosurveillance: Turning Promising Science into the Tools Needed in the Field

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Jennifer B. Nuzzo, Kunal J. Rambhia, Samuel B. Wollner, Amesh A. Adalja, Eric Toner,
Anita Cicero, and Thomas V. Inglesby, September 2011         

Executive Summary: The Need to Improve Our Global Diagnostics Tools

Jump to: Purpose | Analysis and Workshop | Findings | Recommendations | References

The discovery of the 2009 H1N1 influenza pandemic and the emergence of other diseases such as SARS have highlighted the important role that diagnostic tools can play in improving the surveillance of infectious disease threats at the population level. Experiences with these events have shown that recognition of outbreaks, management of epidemics, and development of countermeasures can depend heavily on having access to highly specific surveillance information that is typically obtained from testing clinical specimens. Consequently, the rising threat of emerging diseases and concern about biological weapons has led to an emphasis in governments on improving laboratory and diagnostic capacity in order to improve global biosurveillance for infectious diseases.1

The lack of accurate, durable, and reliable diagnostics is a fundamental challenge in global biosurveillance. Insufficient diagnostic capacity in much of the world leads to no or faulty diagnoses, inappropriate treatments, and misreporting of disease prevalence. In many countries, public health laboratories lack the necessary funding, personnel, and tools to conduct disease surveillance. In light of these challenges, the World Health Organization (WHO), the Institute of Medicine, and other organizations have independently concluded there is an urgent need to develop tools to improve diagnostic capacity both in and outside of laboratory settings.2-6

There is increasing interest among U.S. government agencies in accelerating the development of infectious disease diagnostic technologies to enhance biosurveillance. In 2009, the U.S. National Security Council (NSC) identified enhanced disease surveillance, detection, and diagnosis as priority goals that the United States government (USG) should work toward for the purposes of improving national security and improving the ability to report any public health emergency of international concern.1 This NSC strategy calls on international partners to build surveillance, diagnostic, and detection capacity to help countries fulfill their requirements under the International Health Regulations (IHRs).

In addition to being important for global biosurveillance, improved diagnosis of infectious diseases is also a key goal of a number of global health programs. The Obama Administration’s Global Health Initiative includes efforts to promote the development and acquisition of infectious disease diagnostic tools.7,8 Intergovernmental organizations (IGOs) and nongovernmental organizations (NGOs), such as the World Health Organization (WHO), the Foundation for Innovative New Diagnostics (FIND), and PATH, have prioritized clinical diagnostic technology procurement, regulation, and training for high-burden but underdiagnosed diseases, such as tuberculosis.9

Purpose

Given this increasingly recognized need to improve global diagnostics, the Center for Biosecurity (the Center) conducted an analysis of high-level policy issues that affect diagnostics development and a broad spectrum of diagnostic technologies that are needed for global biosurveillance. The project’s aims were to identify:

  1. specific ways in which the USG can address global biosurveillance goals through the strategic application of diagnostic technologies;

  2. resources necessary to support the deployment of diagnostic technologies in the field;

  3. barriers that may limit the development and procurement of infectious disease diagnostics for global biosurveillance; and

  4. recommended USG actions that can improve development and deployment of diagnostic tools for biosurveillance.

Analysis and Workshop

To inform this analysis, the Center held a series of discussions with leaders in the field of disease surveillance from academia, industry, IGOs, NGOs, and the USG. Discussion topics were derived from several sources: extensive review of USG global biosurveillance programs; discussions with thought leaders in this field; and review of the published literature, key policy analyses, and reports from IGOs and NGOs, such as WHO, the Gates Foundation, and the National Academy of Sciences. These discussions focused on high-level goals of USG involvement in global biosurveillance, specific host country needs, market and regulatory factors in the development of diagnostic tests, and opportunities to enhance USG engagement in biosurveillance through diagnostic development and deployment.

The Center completed a Preliminary Analysis Report to provide a synthesis of the literature and information obtained during our conversations with experts. Those findings were used to facilitate the discussion for a workshop on February 17, 2011, with more than 50 participants from academia, industry, IGOs, NGOs, and the USG (see Appendix A, page 24). Senior staff and leadership from Defense Threat Reduction Agency, the Center, and The Tauri Group participated. Consensus was not sought among workshop participants, but the workshop served as a forum for in-depth discussion of goals, needs, challenges, and priorities for USG support of diagnostics for global biosurveillance. This report presents a synthesis of the Center’s scientific and policy review, a synopsis of the workshop discussions, and brief summary conclusions from the Center. The project was funded by DTRA Chemical & Biological Technologies Directorate (DTRA/RD-CB) through The Tauri Group.

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Findings

Finding 1: There are multiple diagnostic tools that could improve biosurveillance; choosing the right one will depend on what we are trying to achieve.

There are a number of major goals of global biosurveillance, including:

  1. Informing and improving clinical diagnosis and treatment of disease in patients and among U.S. civilians or military personnel in a given country;

  2. Assessing disease trends in other countries;

  3. Facilitating the detection of and response to outbreaks of known infectious diseases;

  4. Facilitating the detection of and response to outbreaks caused by new and emerging pathogens; and

  5. Anticipating or predicting future disease threats.

At a general level, these goals could all be more effectively pursued if there were better infectious disease diagnostic tools. At a specific level, the different goals of global biosurveillance require the collection of distinct types of data and different approaches to information gathering and analysis. The diagnostic tools needed for these biosurveillance goals are likely to possess different operating characteristics and involve separate development and procurement pathways.

Finding 2: There are many promising new diagnostic technologies, but specific user needs should determine which technologies are deployed and where.

The Center found that a strategy for diagnostics development needs to be built on the information needs of the users of these tools. These include:

  1. Molecular-based approaches, which have the potential to decrease the cost and live-agent work needed for diagnosis.

  2. Multi-analyte tests, which show promise for identifying a causative pathogen when the clinical or epidemiologic context is vague or when multiple pathogens can cause similar symptoms.

  3. Host-side diagnostics, a developing field that seeks to interpret unique host-dependent biomarkers for diagnosis. Of particular interest in this field is presymptomatic diagnosis based on unique biomarker signatures.

  4. Culture, the classic microbiological diagnostic method and often considered to be the gold standard, must continue to play a role in a comprehensive diagnostics approach. Work with live agents is not replaceable by other techniques, particularly due to their role in antimicrobial susceptibility testing and vaccine development.

  5. New platforms, including mass spectrometry, microfluidics, paper-based diagnostics, and others, may facilitate the deployment and use of diagnostic approaches in the field. Low-cost, noninstrumented engineering designs for diagnosis are appealing for the conditions and infrastructure of low-resource settings.

Finding 3. Diagnostic tools need to be designed for the environments in which they will be used.

The practical limitations in low-resource settings in developing countries should be considered in implementation of diagnostic tools for biosurveillance purposes. Some of these limitations and challenges include:

  1. Lack of trained staff and difficulty in retention of skilled microbiologists due to lack of incentives for work in low-resource settings.

  2. High cost of reagents and diagnostics, which in some cases favors empirical diagnosis over laboratory confirmation.

  3. Limited infrastructure, including availability of clean water, reliable power supply, and cold storage, which can disrupt testing and cause unreliable results.

  4. Lack of technologies for communicating results to a central authority and back to healthcare providers for administering proper treatments, which can impede proper understanding of clinical and epidemiologic characteristics.

  5. High cost of collecting and transporting viable samples under appropriate regulations, which can limit the facilities and/or distance from collection where diagnostic tests must be performed.

  6. Implementation of biosafety protocols and maintaining security at laboratories, which can add cost that limits the number of facilities available to provide diagnostic services.

Finding 4. Regulatory challenges have slowed the development of diagnostics needed for global biosurveillance.

A robust and strong regulatory process is necessary to ensure that diagnostic tests produce accurate and reliable results. Ineffective, unreliable tests undermine the USG biosurveillance mission. While the U.S. Food and Drug Administration (FDA) represents the global standard for diagnostic test evaluation, improvements in this framework could facilitate the development of products without sacrificing quality and accuracy of tests. There are a number of considerations pertaining to regulatory affairs:

  1. Alternative pathways to market exist, including the European Medicines Agency (EMA), WHO Prequalification, or the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR). Some of these pathways may be more expeditious than FDA approval but are not as rigorous.

  2. Within the U.S. regulatory structure, a fundamental challenge is lengthy review times that increase costs and delay return on investment for diagnostic test developers. However, recent FDA initiatives indicate that improvements that will facilitate regulatory review are forthcoming.

  3. Emergency Use Authorizations (EUAs) are a potential mechanism for marketing of a diagnostic test during an emergency, without full FDA review. EUAs are limited by the inability to distribute tests and train staff prior to the declaration of an emergency. However, changes to the EUA process are being developed and are expected to resolve those issues.

  4. Evaluation of multi-analyte tests has been difficult, partially due to the unknown clinical applications of these tests and unclear burden of proof needed to validate their efficacy and reliability. However, following recommendations from the Medical Countermeasure Review released in August 2010, the FDA has established an Action Team dedicated to clarifying regulatory requirements for multi-analyte tests.

  5. Evaluation and clearance of tests can also be limited when tests rely on privately maintained gene banks, whose quality and completeness are unknown. For some pathogens, lack of availability of viable samples can impede validation and clearance of tests. Publicly maintained gene banks and sample collections could improve and facilitate diagnostic development.

Finding 5. There are major barriers to the advanced development of global diagnostics.

The global market for in vitro diagnostic tests is substantial, estimated to be $44 billion in 2010.10 The economic drivers in this market, however, are not favorable to the missions of global biosurveillance, particularly in developing countries. There are a number of market factors that influence how companies invest in diagnostics that should be considered as the USG decides how to advance global biosurveillance.

  1. Incentives are few for developing cheap, deployable tests for low-resource settings in the developing world. Markets are defined by demands in developing countries, mostly for laboratory-based diagnosis of chronic disease, sexually transmitted infections, cancer, and diabetes. There are additional costs and technical difficulties associated with ruggedizing diagnostic tests for use in harsh, low-resource settings. Without reliable and predictable markets, private industry will remain reluctant to develop diagnostics needed for global biosurveillance.

  2. USG funding of development of diagnostic tests emphasizes early research, but sufficient funding for clinical trials and advanced development is not available. Because of this gap in advanced development funding, there is a ?cliff of death? for prototype diagnostics that never become commercially manufactured.

  3. Development of diagnostics could be facilitated by the creation of standards. Experts suggest that performance standards, platform standards, and operational standards could all reduce costs of development and reduce time to market. While efforts to create standards are under way, there are some concerns as to whether standards for diagnostics are attainable or how they might be used.

  4. Investments in diagnostics must be supported in the long term to build and maintain successful programs. Due to staff turnover and the need for equipment maintenance, continued funding for training, equipment servicing, and purchase of reagents is crucial to long-term success.

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Recommendations

1. Specific USG global biosurveillance goals should drive USG investments in diagnostics.

Each of the USG’s biosurveillance goals is distinct and may require different technological approaches. In light of these different needs, the USG should begin any effort to develop or procure new diagnostic tools with an assessment of how a new diagnostic tool can meet an explicit goal of USG biosurveillance. This analysis should include an assessment of user needs and the extent to which a proposed technology is likely to improve the user’s routine diagnostic work and, therefore, is likely to be adopted by the intended user.

2. The USG will need to invest in a mix of diagnostic technologies in order to meet all of its global biosurveillance goals.

Recent advances in molecular-based approaches and the development of new platform technologies offer the promise of expedited testing of clinical specimens, simultaneously testing for multiple pathogens, and testing in environments outside of the laboratory. Such developments are important and necessary for improving the availability of diagnostic information across the globe. Even with these new approaches, classic techniques, such as culture-based methods, will still be needed in many parts of the world. Therefore, the USG should consider investing in a range of diagnostic technologies. A diversified investment strategy will help to ensure the USG obtains the right mix of diagnostic technologies to help meet all of its surveillance goals.

3. The development of diagnostic tools should be accompanied by a plan for how these devices will be implemented and maintained in the field.

Prior to deploying any diagnostic device in the field, the USG should ensure that there are: (1) adequately trained staff to operate the device; (2) appropriate infrastructure (e.g., power, water, temperature) to support the operation of the device; (3) adequate availability of ancillary resources to support the use of the device (e.g., testing reagents and other supplies); (4) adequate and feasible biosafety and biosecurity plans; and (5) appropriate patient therapies to respond to diagnostic test results.

4. Diagnostic devices that are to be used for biosurveillance should come equipped with an ability to relay data from point of testing to a central public health authority.

In order to best contribute to the biosurveillance mission, diagnostic devices should be accompanied by a plan for how the data from these tools will be collected and relayed to a central health authority. Although it may not be difficult to equip diagnostic devices with technologies that allow for electronic reporting of data to a surveillance system, the inclusion of such data-capture and -reporting capabilities has to date not been a priority in efforts to develop new infectious disease diagnostic tools.

5. The USG should work to improve the process for approving multi-analyte tests and for granting Emergency Use Authorization for diagnostic tests.

In recent years, the FDA has embarked on a number of new initiatives to expedite and streamline the process for clearing in vitro diagnostics. The FDA announced the creation of Action Teams to analyze the process for clearing multi-analyte tests. These teams should give strong consideration to how to expedite clearance of multi-analyte tests, as there is need for such devices in much of the world.

The FDA has also developed a program for granting Emergency Use Authorization for devices and medicines that are likely to be needed during public health emergencies. Additional modifications to this program are necessary to ensure that diagnostic tools that receive EUA are able to be integrated into outbreak response plans and surveillance programs. One needed change is to allow for pre-emergency training and proficiency testing of EUA devices.

6. The USG should help to improve the regulatory approval of diagnostic devices by supporting efforts to strengthen gene banks and to increase the availability of clinical samples.

In the absence of data quality standards to ensure that information contained in public and private sector gene banks is accurate, it will continue to be difficult to evaluate diagnostic technologies that must use these databases to demonstrate testing performance. To expedite this process, the USG should explore how it may best support efforts to ensure the quality of information contained in gene banks that are used to demonstrate the validity of diagnostic devices.

To improve the availability of clinical samples, particularly for rare diseases, for companies and for researchers who are working to develop new infectious disease diagnostic tools, the USG should explore ways to support the creation of sample repositories. The Centers for Disease Control and Prevention (CDC) may be an appropriate place to locate and maintain such a repository.

7. The USG should consider ways of bridging the diagnostics development “cliff of death? by increasing support for advanced development and diagnostic procurement.

The diagnostic tests that are needed for global biosurveillance have a limited or nonexistent market and, therefore, will require incentives to develop. While current USG investments in diagnostic tests emphasize early scientific research, additional funding is needed to help companies and researchers with promising technologies address challenges encountered during advanced development, clinical evaluation, and scale-up manufacturing.

Any effort to develop and procure diagnostic devices to enhance global biosurveillance will require sustained investments. Initial costs for development of a number of products need to be supported by maintenance, purchase of reagents, and training.

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References

  1. The White House. National Strategy for Countering Biological Threats. November 2009. http://www.whitehouse.gov/sites/ default/files/National_Strategy_for_ Countering_BioThreats.pdf. Accessed May 16, 2011.

  2. Hay Burgess DC, Wasserman J, Dahl CA. Global health diagnostics. Nature 2006 Nov 23;444 Suppl 1:1-2.

  3. Institute of Medicine, Forum on Microbial Threats. Global Infectious Disease Surveillance and Detection: Assessing the Challenges—Finding Solutions, Workshop Summary. Washington, DC: National Academies Press; 2007. http://www.nap.edu/catalog/11996.html. Accessed June 27, 2011.

  4. RAND Corporation. Estimating the global health impact of improved diagnostic tools for the developing world. Research Highlights 2007. http://www.rand.org/content/dam/rand/pubs/research_briefs/2007/RAND_RB9293. pdf. Accessed April 11, 2011.

  5. World Health Organization. Diagnostics for Tuberculosis: Global Demand and Market Potential. 2006. http://apps.who.int/tdr/publications/tdr-research-publications/diagnostics-tuberculosis-global-demand/pdf/ tbdi.pdf. Accessed June 27, 2011.

  6. Urdea M, Penny LA, Olmsted SS, et al. Requirements for high impact diagnostics in the developing world. Nature 2006 Nov 23;444 Suppl 1:73-79.

  7. United States Government Global Health Initiative. The United States Government Global Health Initiative Strategy. 2011. http://www.ghi.gov/documents/organization/157796.pdf. Accessed July 7, 2011.

  8. The United States President’s Emergency Plan for AIDS Relief. BD/PEPFAR lab-strengthening initiative marks progress in fight against HIV/AIDS and TB in sub-Saharan Africa. July 19, 2009.
    http://www. pepfar.gov/press/releases/2009/126214.htm. Accessed May 16, 2011.

  9. Foundation for Innovative New Diagnostics. Delivering on the Promise: Summary of Five Years of Progress Towards More Effective Diagnostic Tests for Poverty- Related Diseases. 2008.
    http://www. finddiagnostics.org/resource-centre/find_ documentation/delivering-on-the-promise-five-years-of-progress.html. Accessed May 16, 2011.