7

Exploring Potential Policy Options

Workshop participants discussed a “menu” of potential policy options (Box 7-1) for incentivizing the development and use of rapid diagnostics, important issues to consider, and next step opportunities.

POLICY OPTIONS

Mark McClellan (Duke Margolis Center for Health Policy) laid out a “menu” of potential policy options to encourage the development and appropriate use of rapid diagnostics. Panelists, each representing a different stakeholder perspective, made brief remarks, followed by a discussion moderated by McClellan. The discussion is presented by topic area rather than by speaker. The panelists were:

• Industry perspective: Phyllis Arthur (Vice President, Infectious Diseases & Emerging Science Policy, BIO)
• Research perspective: Sarah McClelland (Health Policy Analyst, U.S. Department of Health and Human Services)
• Policy perspective: Jaclyn Levy (Director, U.S. Policy, AMR Action Fund)
• Law and economics perspective: Kevin Outterson (Professor of Law, Boston University, Executive Director, CARB-X)

Before exploring the suggested policy options outlined in Box 7-1, several speakers discussed why policy levers are appropriate or necessary for spurring diagnostic development. Arthur stated that one barrier to

diagnostic development lies in the valuation of diagnostics and antibiotics; these products are essential to the public’s health and for the longevity of effective treatments, but the market does not value them in this way. Given this reality, Arthur noted the options are to either allow diagnostic products to be valued for what they bring to the marketplace or to find substitutions for the valuation that allow companies to invest in the work without losing money. Policy interventions can be used to address the valuation issue and encourage investment in the area.

On a similar note, Outterson said that while the use of rapid diagnostics has benefits—including better care, reductions in cost of care, and curtailing

AMR—the financial return for using a diagnostic does not usually flow back to the entity that makes the initial payment. Diagnostics are currently more expensive than empirical prescribing an antibiotic, said Outterson, so there is not a financial incentive for key stakeholders to incorporate the use of these products. As noted by Anthony So in Chapter 5, bundling the development, use, and reimbursement of diagnostics with drugs may be one way to manage this issue.

Outterson highlighted that hospitals are reimbursed through Medicare based on a DRG system. Patients are classified based on DRGs, which determines how much money the hospital will receive on a per case basis.

The DRG system is designed to drive cost-cutting for inpatient expenses, such as nursing, facilities, food, bed, and pharmacy costs. Patients with a particular type of bacterial infection may be assigned the same DRG whether they are prescribed a relatively inexpensive generic antibiotic or if the hospital deploys a costly new diagnostic test that determines the generic drug is not effective, in which case the hospital may be obligated to prescribe a more expensive antibiotic. Each step of this process, said Outterson, incurs costs—space for the diagnostic test, staff to run the test, expense of running the test, and prescribing a more expensive drug—without additional reimbursement through the DRG system. When a hospital CEO or CFO considers the financial implications of adopting a new diagnostic tool, there are more costs to be controlled than incentives for improving patient care.

In the emergency department, the financial incentives look a bit different, said Outterson. A rapid diagnostic could help a provider to make a quick decision about whether to admit a patient or send them home. Testing in the ED is paid for through CPT codes, or if a patient is admitted that cost is rolled into the DRG payment. CPT codes can be confusing for new diagnostics, he said, but if a test is billed correctly and a patient is not admitted, it could result in a small positive margin for the ED.

According to Outterson, given these types of misaligned incentives, hospitals are not financially motivated to adopt new (more expensive) diagnostic tools; add newer antibiotics to AST panels and breakpoints; add new antibiotics to the hospital formulary; use a higher-priced antibiotic; or identify a hospital-associated infection. As a result, timely diagnosis and appropriate treatment for patients are often delayed.

Encouraging the Development of Rapid Diagnostics

Incentives to Promote Coordination, Cooperation, and Efficiency

In response to the ongoing COVID-19 pandemic, the diagnostics industry has built up core capability, said Arthur, and policy solutions should leverage this capacity and direct resources towards better point-of-care rapid diagnostics. Policies and approaches that can help promote coordination include accelerator programs (e.g., CARB-X), clinical trial networks, master study protocols, and coordinating organizations, said McClelland. She pointed to the PACCARB, which recommended the following:

McClelland said this list could help spur collaboration between diagnostic companies and stakeholders in the AMR arena and accelerate the development of diagnostic tools. Levy added that challenges like the Rapid Acceleration of Diagnostics (RADx) and the NIH/ASPR AMR Diagnostic Challenge, which have been successful in accelerating the development timelines for other products, could be applied to AMR diagnostics to promote collaboration and partnerships between companies and funders. Crowdsourcing and citizen science also present opportunities for public-private partnerships. Advocacy and patient coordination are particularly challenging with infectious diseases due to the variety of patient groups, said Levy, but coordinating these groups within the AMR space and connecting their experiences to the need for diagnostics continues to be important work.

Regulatory Approaches

Regulatory approaches, said McClelland, could include reforms that remove barriers and simplify the process of obtaining regulatory approval, similar to the regulatory flexibility that the FDA showed during the COVID-19 pandemic. In addition, clinical trial networks with common rules and shared IRBs could reduce the regulatory burden of test approval. Arthur suggested that given the ongoing pandemic, there may be more pressure for companies to concurrently develop rapid diagnostics alongside new therapeutics. Levy highlighted the need for balance between the regulatory system and the rapid deployment of new technologies. She added that there is a need to retain the ability of clinical laboratories to develop rapid diagnostics, particularly for pediatric and immunocompromised patient populations. There may be opportunities to address these needs, in part, through post-market data and real-world evidence.

New Incentives

Tax credits are one pull incentive that PACCARB has recommended, which would pair funding for the development of new antibiotic susceptibility tests with the development of new antibiotics by providing a tax credit for a portion of clinical testing expenses (PACCARB, 2017). Arthur pointed to the need to incentivize developers of antibiotics to work with diagnostic companies. She suggested that incentives could focus on a core set of pathogens that would most benefit from a paired diagnostic and drug. Outterson added that drugs and diagnostics should be developed in similar time frames because it could take years after the introduction of a new drug before a physician could get information about susceptibility or resistance.

An additional benefit of co-development of drugs and diagnostics is that it can reduce the cost of clinical trials, said Arthur; a diagnostic allows patients to quickly be differentiated and eligible patients enrolled in relevant clinical trials. Jean Patel (Principal Scientific Affairs, Microbiology, Beckman Coulter Diagnostics) cautioned that while co-development can be advantageous, there are also risks involved. She mentioned that she has seen cases in which diagnostics were developed or redesigned to include a specific drug, but the drug did not make it to market. These experiences could serve as a disincentive for these types of partnerships, but policy approaches could help mitigate some of these risks.

Arthur stressed that incentives should be focused on the most urgent antimicrobial threats and that putting incentives toward the right drug and the right tool being developed and deployed “at the same time” will result in the best outcomes in healthcare. She added that there are lessons to be learned from the oncology field. When companies are creating an oncology treatment, they are encouraged to develop a companion diagnostic that allows clinicians to use the product on the right patient to optimize outcomes. Using this approach for antibiotics, said Arthur, means that clinicians would have the data they need to direct treatment to the patient rather than “empirically trying every antibiotic in the pharmacy.” A rapid diagnostic that would lead to the most effective drug being prescribed to a patient, she said, is the “holy grail” of what stakeholders in rapid diagnostic development are trying to achieve.

Encouraging Uptake and Use of Rapid Diagnostics

Demonstrating Clinical Value

According to McClelland, successful development and regulatory approval of a diagnostic test is only the first hurdle; to be impactful, the test must be appropriately used during patient care. There are a variety of policy approaches for incentivizing the uptake of diagnostics, said McClelland, including policies in the areas of clinical value, guidelines, and reimbursement reform.

Clinicians want a test that will make a difference in the care of their patients, said McClelland. If doctors and administrators had more information about what works, said Outterson, uptake would improve. Policy approaches that could increase the likelihood that the diagnostics that are developed are taken up by clinicians include:

• Funding for research that investigates the clinical outcomes and benefits to patients related to diagnostics (Outterson);

• Promoting collaboration between diagnostic companies and other stakeholders to help ensure optimal test development to meet clinical needs and to increase the likelihood of adoption of test (McClelland);
• Providing clinician education on the use and interpretation of diagnostic tests to spur uptake in clinical practice (McClelland);
• Increasing collection and analysis of post-market data and real-world evidence (Levy).

Development of Guidelines

Several speakers mentioned the need for timely guidelines for new diagnostics, and how these could prompt improvements in uptake and reimbursement, said McClellan. Arthur said that the value of clinical guidelines is that they set a drug or a diagnostic apart from others and empower clinicians to get access to the product for their patients. McClellan asked panelists how policy could be used to support rapid guidelines development when there is a breakthrough diagnostic. Levy said that during the COVID-19 pandemic, IDSA was able to get guidelines out “incredibly rapidly,” but it took a global emergency and an enormous amount of effort. Guideline development takes manpower, time, and work, and is usually carried out by volunteers. There is a need for more resources and expanded capacity to enable guidelines to be developed more quickly.

Reimbursement Reform

Once a product reaches the market, said Levy, clinical uptake can be a significant challenge due to misaligned financial incentives—for example, hospital administrators are reluctant to use a $50 test to prescribe a $5 antibiotic. While using a diagnostic to find the right antibiotic has the potential to save money in terms of patient care and patient outcomes, said Levy, the current reimbursement structure does not reflect this value. Realigning incentives to encourage uptake will require reimbursement reform for diagnostics; Arthur added that reform for reimbursement of antibiotics may be necessary as well. Speakers suggested several policy approaches:

• A shift toward a reimbursement system that prioritizes patient outcomes rather than cost minimization (McClellan);
• A reimbursement-plus system to realign reimbursement with value (McClelland);
• Using conditions of participation in Medicare to enhance diagnostic use; this approach was “transformative” for antibiotic stewardship (Outterson).

Several speakers suggested that new technology add-on payments (NTAPs) could play a role in incentivizing the uptake of diagnostics.¹ However, Outterson pointed out that these have not generally been effective for AMR-related products thus far. NTAPs were created in 2001 to deal with the unanticipated consequences of Medicare reform, and they provide separate reimbursement for up to 50 percent of the added cost to hospitals for selected clinically valuable products for two to three years. However, the funds do not return to the cost center (hospital pharmacy or lab), which undermines the goal of the policy. In the hospital laboratory, he said, there are four major financial concerns: space, time, people, and costs. A company with a new diagnostic tool is asking for all four of these and any extra reimbursement goes to another account in the hospital. For example, if an antibiotic diagnostic has a NTAP, the NTAP may reduce the cost of each test by $50. However, the hospital still incurs the costs of buying the technology, conducting the tests, and potentially paying for more expensive medications. Even with the NTAP, Outterson said, the diagnostic may cause the hospital to lose money on a patient. Evans agreed that in his view, NTAPs are not effective because they do not offer enough of an incentive, and the likelihood of a provider receiving the passthrough payment is low. However, he said, there is an opportunity to bolster the program and remove some of these barriers.

Considerations for Policy Interventions

In addition to discussing specific policy options, panelists reflected on a variety of issues to consider when implementing policies directed at improving the development and uptake of diagnostics for AMR.

Role of the Federal Government

The federal government has a unique and important role to play in incentivizing development and uptake of diagnostics, said Levy. The federal government can use its resources and position to fund research, create tax credits, change reimbursement policies, simplify regulatory requirements, and facilitate collaboration among developers and clinical investigators. In addition to these critical incentives, the federal government could develop a list of the highest priority areas in which diagnostics are needed (similar to WHO’s Essential Diagnostics List²). This list could help guide both public and private decisions about funding, research, and incentives, said Levy.

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¹ See https://www.federalregister.gov/documents/2001/09/07/01-22475/medicare-program-payments-for-new-medical-services-and-new-technologies-under-the-acute-care (accessed January 27, 2023).

² See https://www.who.int/teams/health-product-policy-and-standards/assistive-and-medical-technology/medical-devices/selection-access-and-use-in-vitro (accessed January 27, 2023).

Levy said that the types of incentives discussed at the workshop provide a good opportunity for engagement across different agencies and organizations. For example, NIAID has experience with small-business grants, while the FDA and Internal Revenue Service (IRS) have experience with tax credits for clinical testing expenses (i.e., the Orphan Drug Tax Credit³). Partnerships and collaborations are critical for moving efforts forward, she said, and there are existing models that can be leveraged for AMR. For example, RADx initiative at NIH supported innovative and nontraditional diagnostic approaches for COVID-19;⁴ a similar initiative could be explored for AMR diagnostics. PACCARB and the CARB Task Force are examples of collaborative bodies convened by the government that are working on issues surrounding AMR (Box 7-2).

An Ethical Dilemma

Burnam suggested that if a brand-new drug for MRSA were released, it would be the clinician’s ethical responsibility to “lock it in a safe” and not use it until it is absolutely needed. As soon as people are exposed to a new drug, the bacteria will begin evolving resistance, he said, so from a “do no harm” perspective, a clinician should be extremely cautious about using new drugs. However, if a drug does not get used, the pipeline of new drugs dries up because the business model is unsustainable. Arthur said that this is a “chicken or the egg” problem, in which physicians feel like they have to “hold everything behind glass” because they want to have something in reserve when resistance occurs. McClellan said that this dilemma demonstrates the value of having accurate, rapid diagnostics that can give physicians confidence about using a specialized drug in a particular patient who needs it.

Global Implications

Even if the problems discussed during this workshop were resolved, there would still be an ongoing AMR pandemic throughout the rest of the world, stated Bausch. Most of the solutions suggested so far are not applicable outside of the United States. For example, even if a diagnostic were developed that cost two dollars, amoxicillin can be purchased on the market for 50 cents. Whether the antibiotic works or not is “almost immaterial,” said Bausch, because patients and clinicians are generally inclined to use the easier and more affordable solution. In the context of an LMIC, Bausch suggested that it will take long-term investment

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³ See https://www.irs.gov/forms-pubs/about-form-8820 (accessed January 27, 2023).

⁴ See https://www.nih.gov/research-training/medical-research-initiatives/radx (accessed January 27, 2023).

and creative financing and approaches that are not entirely based on short-term economics. Arthur added that regardless of the incentives for development and uptake, behavioral change is needed, and this applies to care settings in the United States and LMICs. Clinicians and patients hold certain views about antibiotic use, and these views impact their behavior: “The right drug in your hands” will not make a difference without behavior change, she said.

CONSIDERING A PATH FORWARD

AMR is a complex term that involves multiple bacterial species and multiple clinical syndromes, so there will likely need to be multiple ways for diagnostics to help manage AMR, said J. Patel. She noted, for example, that the bacterium that Mallory Smith was infected with—Burkholderia cenocepacia—is not on the list of CDC antibiotic resistance threats.⁵ For an individual patient, antimicrobial resistance is a problem regardless of which bacterium is causing their infection, so diagnostic-based solutions should address AMR broadly and across all patient populations. At the same time, J. Patel pointed out, clinical microbiology laboratory staff has been decimated because of the ongoing COVID-19 pandemic. “We cannot go on with diminished technical expertise in infectious disease diagnostics,” she stated, and replenishing the workforce is a responsibility that falls on all sectors of diagnostics and patient care.

In considering the path forward, panelists identified a few areas for which next steps could improve the development and uptake of AMR-related diagnostics: leveraging COVID-19, addressing regulatory barriers, policy reform to incentivize diagnostic development and use; prioritization of efforts based on pathogen, syndrome, or care settings; and collaboration to share information and resources, establish common metrics, and mobilize people and organizations to take action.

Leveraging COVID-19

“We are in a technology revolution, but we are also in an AMR pandemic” said Robin Patel (ID Physician, Clinical Microbiology Laboratory Director, Mayo Clinic). In response to the ongoing COVID-19 pandemic, there were remarkable advances in diagnostics development. There is an opportunity, said R. Patel, to apply lessons learned from COVID-19 towards AMR. This should be done in an expeditious way so that patients can get the treatments they need. Arthur added that the COVID-19 pandemic demonstrated how industry can make faster, better, and easier-to-use diagnostics. Leveraging these core capabilities to improve point-of-care and at-home diagnostics and ramping up partnerships for the development and use of diagnostics are two promising options for the AMR space.

Addressing Regulatory Barriers

Emerging technologies offer an opportunity to measure and see things in a different way than before, said Ribhi Shawar (Branch Chief, Division

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⁵ See https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf (accessed February 6, 2023).

of Microbiology Devices, Office of In Vitro Diagnostic and Radiological Health, Center for Devices and Radiological Health, FDA). However, these technologies come with challenges for regulators, particularly in determining a comparative reference method. For example, during the COVID-19 pandemic, a new test was proposed that could diagnose COVID-19 through the breath.⁶ The only existing breath-based test, said Shawar, was a test for H. pylori.⁷ He said that this required regulators to really think about how to evaluate a test that was operating in a “totally different paradigm.” Collaboration and coordination are critical when developing, evaluating, and implementing these new technologies: some stakeholders bring expertise, others bring facilities and tools, and others bring specimen banks. The field will not advance without collaboration, he said.

Van Meter said that a program to provide transitional coverage for emerging technologies could help technologies that have been cleared and received breakthrough status from the FDA. Such a program might support device and diagnostic manufacturers work collaboratively with the government to generate evidence. However, she noted, this type of approach would not necessarily ensure an appropriate reimbursement rate or a market. Shawar added that there is an existing “pre-submission” program at the FDA that allows developers to ask questions before they formally submit a Premarket Approval Application.⁸ This program helps developers conduct studies and gather evidence in a way that will be amenable to the FDA. J. Patel agreed that these types of programs for emerging and innovative technologies are useful in the AMR space, in part because clinical care practices are constantly evolving.

Addressing Reimbursement Barriers

Susan Van Meter (President, American Clinical Laboratory Association) offered a few suggestions for how reimbursement barriers to the development and uptake of diagnostics could be addressed through CMS. First, Medicare has conditions for participation that require antimicrobial stewardship programs in the inpatient setting. Work could be done to bolster these requirements and build diagnostic stewardship programs into conditions of participation. Another approach could be to include diagnostic stewardship as part of a value-based payment initiative. For example, a program launched by the Affordable Care Act holds back two percent

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⁶ See https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-covid-19-diagnostic-test-using-breath-samples (accessed January 27, 2023).

⁷ See https://www.fda.gov/media/157723/download (accessed January 27, 2023).

⁸ See https://www.fda.gov/regulatory-information/search-fda-guidance-documents/requests-feedback-and-meetings-medical-device-submissions-q-submission-program (accessed January 27, 2023).

of inpatient hospital payments and uses the money to reward hospitals for advancement compared to peers and improvement compared to baseline.⁹ She highlighted that it would be important that incentive programs not be used to penalize hospitals. Underserved hospitals that are struggling for resources should be given the resources they need rather than penalized for not meeting certain metrics.

In ambulatory settings, said Van Meter, Medicare’s Merit-Based Incentive Payment System (MIPS) for physicians could be used to encourage ambulatory diagnostic stewardship programs, particularly in areas that are most impacted by inappropriate prescribing. The Centers for Medicare and Medicaid Innovation Center has “extraordinary authority” to waive rules and regulations for pilot programs, she said. Their primary focus is on improving quality of care while reducing cost, but they also have authority to implement programs that increase costs to improve care. Together, Medicare and Medicaid reach a very high proportion of Americans throughout the country and leveraging this mechanism could help develop evidence about the value of diagnostics for AMR across the patient population.

Van Meter added that from her perspective, one of the most pressing priorities is to pass the Saving Access to Laboratory Services Act (SALSA)¹⁰ to prevent cuts to Medicare payments for laboratory tests. Medicare is a large market, she said, and so SALSA would provide a more predictable pathway forward for developers. Another approach, said Van Meter, would be to encourage CMS to use existing authorities to put in place Medicare and Medicaid pilot programs that leverage diagnostic stewardship programs across communities. Finally, she pointed to Independent Test Assessment Program (ITAP), which helped small and large companies pull together diagnostic submissions to the FDA in an expedited fashion during the COVID-19 pandemic. A similar model, made permanent and adequately funded, could help ensure that there is a fast-track mechanism for getting needed diagnostics through the regulatory process as quickly as possible. Diagnostics account for two to three percent of total healthcare spending but drive around 70 percent of clinical decision-making (Rohr et al., 2016). The “investment in diagnostics is so worth it across the board,” she said.

Pursuing Innovative Approaches

Joseph Larsen (Vice President, Clinical Development, Locus Biosciences, Inc.) said that innovative diagnostics in the AMR space would not only improve treatment with traditional antibiotics but would also contribute

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⁹ See https://www.cms.gov/newsroom/press-releases/affordable-care-act-program-improve-hospital-care-patients (accessed January 27, 2023).

¹⁰ Saving Access to Laboratory Services Act, HR 8188, 117th Cong., 2d sess. (June 22, 2022).

to the development and use of nontraditional treatments such as genetically engineered bacteriophage. For example, Larsen’s company is currently enrolling UTI patients in a clinical study for an Escherichia (E.) coli phage “cocktail.”¹¹ Before enrollment and randomization, it must be confirmed that the patient is infected with E. coli. Current testing adds a delay of three days between the administration of a test and the interpreting of results after which a patient can enroll, and the trial itself is testing a five-day dosing regimen. Because of this time commitment, he said, many patients simply take their antibiotics and “go home.” A diagnostic that would quickly confirm E. coli infection would remove some of the barriers to enrollment and allow evidence to be collected more quickly on these new approaches. Launches of new antibiotic agents over the last decade have been “atrocious” from a commercial standpoint, said Larsen, but innovative diagnostics have the potential to improve the commercial prospects for both new antibiotics and nontraditional approaches to infectious disease.

Levy agreed that innovative and nontraditional approaches to diagnostics are needed to meet the challenges in the area of AMR and diagnostics, including workforce shortages, the lack of a coordinated and robust patient advocacy community, and regulatory barriers. New and nontraditional approaches to diagnostics include:

• community wastewater surveillance and analysis to identify pathogens and measure the spread of infection;
• novel analytical platforms (e.g., NGS) coupled with point-of-care, noninvasive sample collection;
• screening and home-based tests;
• integration of AI systems, novel diagnostics, and digital health technologies that can screen, diagnose, monitor, and predict disease severity;
• automatic, real-time detection and tracing to integrate virus-sensing elements with touchscreen or other digital devices.

Innovative approaches to developing diagnostics may also be needed, she said. For example, the AMR Diagnostic Challenge was a federal prize competition that sought innovative, point-of-care diagnostics to combat AMR; the winner received $19 million for a rapid diagnostic for gonorrhea that detected microorganisms and susceptibility to a single-dose antibiotic in under 30 minutes (NIH, 2020). This challenge, said Levy, spurred a number of paradigm-shifting and “moonshot” diagnostics. Another approach for encouraging innovation is crowdsourcing or “citizen science.” This has

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¹¹ See https://clinicaltrials.gov/ct2/show/NCT05488340 (accessed January 27, 2023).

become popular in adjacent fields, said Levy; for example, Foldit¹² is an online video game designed to advance research in protein folding. Foldit is also an example of a strong public-private partnership, she said, as its collaborators include University of Washington, Defense Advanced Research Projects Agency (DARPA), NIH, Amazon, Microsoft, Adobe, and others. A similar approach could be taken to generate data for the development of diagnostics and therapeutics. In fact, said Levy, Adaptive Phage Therapeutics has just announced a challenge to find bacteria that are resistant to their investigational phage bank, with any successful submission receiving $1000.¹³

CLOSING REMARKS

Given that cost underpins many of the challenges raised during the workshop discussions, Trainor suggested that rather than trying to “boil the ocean,” it can be helpful to think about how the community could come together to support focused efforts on specific pathogens, syndromes, or care settings that would have the most impact. Priority areas might include care settings that have demonstrated high levels of inappropriate prescribing or conditions, such as sepsis, for which time has a significant impact on disease progression and patient outcomes. Eder suggested that one area in which investments could make a difference is asymptomatic monitoring. In some care settings, monitoring may not be cost-effective, he said, but in particular settings, such as nursing homes, diagnostics that help monitor patients and detect the onset of infection could support more timely and effective treatment. As an example, Eder suggested that in a retirement facility setting, the use of wearables that detect UTIs could help inform the appropriate and timely use of antibiotics and mitigate the development of more serious conditions.

Trainor, Shawar, and Kester encouraged stakeholders to share information and resources through collaboration. Shawar pointed out that diagnostic developers need access to data, such as genetic information and its correlation to phenotype. Specimen banks are also critical for validating devices, particularly for rare pathogens and rare resistant organisms. Additionally, J. Patel and R. Patel highlighted the need for commonly accepted metrics for improving antibiotic use in hospital settings. If there were metrics upon which hospitals were responsible for improving prescribing, this could change how diagnostics are used and institutionalize

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¹² See https://fold.it/ (accessed January 27, 2023).

¹³ See https://aphage.com/adaptive-phage-therapeutics-announces-the-amr-rapid-challenge-for-the-infectious-disease-research-community-find-a-bacteria-resistant-to-apts-investigational-phage-ban/ (accessed January 27, 2023).

the benefits of appropriate antibiotic use. Trainor and Kester concluded that discussions such as these can help mobilize people, organizations, and the public to engage on the issue of diagnosis and appropriate treatment and take action.