Rapid FDA reviews are only one step in the process of implementing a robust, multi-faceted testing strategy as a key to returning to normalcy during the COVID-19 pandemic. In an extraordinary virtual meeting organized by the Duke-Margolis Center for Health Policy, top diagnostics experts dissected the realities of supply chain reliability, robust data collection, reimbursement, and safety.
Because of COVID-19, two common laboratory technologies, PCR and serology are now ordinary dinner table conversation, and we know more about the epidemiology of “flattening the curve” than many healthcare providers did a few months ago. The public is clamoring for more tests, and regulatory authorities are responding.
Under the FDA’s expedited Emergency Use Authorization (EUA) pathway, a wide range of large and small diagnostics companies are getting clearances for their products in record time, providing key tools in the high-stakes race to solutions for the pandemic that has put the world on pause.
But it’s one step to enable rapid FDA review and another to ensure a robust infrastructure to go with newly approved tests. Although more tests are on the market, much confusion remains on how and when they will get where they are needed and to what extent they will satisfy demand, let alone optimize the information flow. From a business perspective, test suppliers aren’t guaranteed a profit. Although the first-quarter earnings calls beginning in mid-April may shed some light on the economics of testing, the devil is in the details.
An extraordinary virtual meeting of top policy experts, diagnostics industry executives, and government officials organized by the Duke-Margolis Center for Health Policy on March 31 highlighted key bottlenecks and the realities of expanding testing rapidly, even in an environment that is as accepting of disruption as this one. The meeting was moderated by former FDA Commissioner Mark McClellan, MD, PhD, the center’s founding director and one of the nation’s leading health policy experts.
Any discussion of testing as a cornerstone to a fully functioning society has important takeaways for society overall and for medical device manufacturers in particular, as they grasp for information that can help them navigate steep drops in their revenues and the prospect of forecasting their business outlook for the rest of the year and beyond. Key questions on device executives’ minds are when will demand for elective or non-urgent surgeries, which are so important to the healthcare care systems’ bottom lines, as well as to patient well-being, return to normal, and how to manage businesses through a prolonged downturn. If adequate testing holds some solutions, a lot more than regulatory largesse needs to come together.
A Diagnostic Testing Roadmap to Normalcy
Even as the shortcomings of current SARS-CoV-2 diagnosis strategies are apparent, waves of new tests are becoming available in the US. Testing capacity for the virus, at near zero at the beginning of March, approached a cumulative 2.8 million as of April 12, according to The COVID Tracking Project, a new online forum for monitoring testing and other pandemic data—and the numbers grow exponentially by the week.
Almost all the tests currently available apply molecular technologies to diagnose presence of infection based on the virus’ genetic makeup. Serological tests that can differentiate whether people who have been infected by the virus are protected from re-infection—which many experts believe is a cornerstone to any return-to-normalcy strategy—are still largely in development, with scattered use of internally developed laboratory-developed tests (LDTs).
Under a plan put forth on March 28 by the American Enterprise Institute (AEI) and highlighted at the Duke-Margolis meeting, critical components of any return-to-normalcy initiatives include serological testing to gauge exposure and immunity status along with a mix of liberal use of rapid point-of-care diagnostics for identifying both symptomatic and asymptomatic community infections. Same-day molecular diagnostic testing is key for hospitalized patients to isolate those who are positive for SARs-CoV-2 and also of managing healthcare and other essential workers, close contacts of confirmed cases, and outpatients with symptoms.
As the epidemic runs its course, all of these tools are necessary to transition from population-based mitigation strategies to managing the sickest patients, said Scott Gottlieb, MD, the former FDA Commissioner, and a co-author of the AEI road map. Also necessary will be a high-performing disease surveillance system as the nation moves to less restrictive physical distancing for tracking the background rate of infection and identification of community spread, including asymptomatic people.
Robust screening that we have not previously contemplated is necessary because “this virus is not going away. It will be with us until we get a vaccine that can vanquish it” he said. “We will have to adapt our lives in meaningful ways to manage this, which I don’t think the political and financial worlds have yet completely realized. It will inconvenience providers and change practices, but these changes will have to occur–it is a matter of will and funding.”
As of mid-April, most diagnostic testing was still taking place in hospitals, with people waiting for days for results. On the day of the virtual conference, nearly 8,000 people in New York State had tested positive for SARS-CoV-2, or, as Gottlieb noted, 50% to 70% of all tested (by April 14 the positive number in New York had jumped to 202,208 out of roughly 500,000 tested). Estimates for testing capacity requirements vary depending on the analyst and trajectory of the epidemic at a given point in time, but using a heavy flu season as a model, AEI estimates that a minimum of 750,000 SARS-CoV-2 tests a week would be necessary to meet demand, with an optimal expansion to at least one million a week.
The nation seems on track to meet that goal as centralized laboratories and diagnostic test manufacturers ramp up—as of March 30, the cumulative number of tests performed in the US was 959,000. During the week ended April 11, a milestone was reached when for the first time, more than one million tests were conducted, meeting the AEI’s asserted threshold of acceptable standard for weekly community testing volume.
Serological Testing is Slower to Take Off
The role of serological testing, initially overlooked in the early days of the pandemic, is increasingly understood but remains a source of confusion to the public and even many professionals. The serological tests measure SARS-CoV-2 IgG and IgM antibodies, which are proteins in the blood that the immune system produces to fight specific infectious agents. A positive test result indicates previous infection, providing information that helps experts understand the seroconversion rate and titrate public health tools based on results (see Box, “Serology Research Update”).
Preliminary studies, not yet published, show upwards of 10% of healthcare workers have seroconverted, indicating their high exposure to disease, Gottlieb said, explaining that level of seroconversion would not enable herd immunity in the community, which epidemiologists say would be ideal, but it would help hard-hit regions manage their labor forces and mitigation tools.
Serology Research Update
On April 10, the National Institutes of Health (NIH) announced that it is recruiting volunteers without a confirmed history of infection to participate in a seroconversion study that will help inform epidemiological researchers about the extent of infection in the US; the researchers will test blood samples from 10,000 volunteers using an NIH-developed test based on ELISA technology, a commonly used tool for protein analysis.
Two major diagnostics manufacturers have launched antibody tests in recent weeks, both without FDA EUA review. BD announced on March 31 that it will begin commercializing a rapid serology blood test for detection of IgM and IgG antibodies in mid-April. The test was developed by BioMedomics and is being distributed by Henry Schein to healthcare providers in the US.
Abbott Diagnostics announced on April 15 that it is launching a laboratory-based antibody blood test that detects IgG only and is ready for shipping in the US. These launches are allowed under public health emergency guidelines. Abbott said it plans to file an EUA submission for its test. Test performance specifications were not available at press time.
These tests have not to date been available for widespread coronavirus testing, but once validated they could be scaled by layering them into routine blood testing. The problem is that, although some 70 or so manufacturers have announced plans to develop serology tests, according to Canaccord Genuity, as of mid-April, the FDA has approved only one. Others are available as LDTs, and lack EUAs, with concerns remaining about their accuracy. As a result, for now, the FDA is warning that only tests that have been FDA approved should be used as the sole source of determining diagnosis or serology status.
The director of the FDA’s Office of IVD and Radiological Health Timothy Stenzel, MD, PhD, told meeting participants that the agency is taking an “all hands- on-deck” approach to regulating testing, providing guidance to manufacturers. “We welcome all test developers in this space,” he said, noting that his office expected to grant the first EUAs for serology testing by early April.
Panelists also stressed that all testing platforms would be necessary to meet demand, with the bulk of responsibility falling on centralized laboratories that have high-throughput systems to process high volumes of samples. “These things are not either–or,” said Michael Pellini, MD, a managing partner at the venture capital firm Section 32, which invests in next-generation diagnostics companies. He is ex-CEO and chairman of Foundation Medicine, a phenomenally successful cancer genomic testing company that Roche bought in 2018 at a valuation of $5.3 billion. Additional must-haves include stable sources of sampling components, appropriate infrastructure, and test performance validation, whether offered as LDTs or FDA EUA-approved options, he noted.
Pellini emphasized the need going forward for clear reimbursement mechanisms, particularly as related to home testing and for the mechanisms to upload test results to a national database that is accessible to researchers and public health experts in order to better understand the virus and monitor the course of outbreaks (see Box, “Reimbursement Update”).
And none of this will be static. “The database needs to be available for freely open research, both at the academic and industry levels, and the tests will be refined as we learn more about this rapidly evolving world,” Pellini continued, suggesting that one way to ensure data capture is to link provider payments to data collection, so that payments are made after test results are uploaded. “If we have this national database that brings all of this testing information together, it will help us get back to work and help us see our elderly parents. It will help healthcare workers and assisted living workers be able to safely see their patients and folks living in various settings across the United States,” he said.
The Pull and Conundrum Around Home Testing
Rapid, point-of-care and at-home testing can, theoretically, address gaps in information needed for more orderly, real-time clinical decisions, but confusion also exists around their capabilities and limitations. While home tests in particular seem appealing, especially for the asymptomatic population, the FDA has not yet approved any.
There are chain of command issues around sample prep and transport, as well as concerns about adequacy of sampling that raise uncertainties about the quality of home-based diagnostics, according to the experts. That said, the FDA has been remarkably positive about home diagnostic testing as a paradigm and expects to green-light some of those formats in the near term, said Stenzel.
“Since early January, we have been open for test developers and have opened a pathway for CLIA-waived point-of-care finger stick tests,” he said. “We are working with federal partners to make virus samples available for test validation.”
Supply Chain Resiliency Also Key
Supply shortages, especially for low-value, high-volume components, such as reagents, transport media, and nasopharyngeal swabs, as well as personal protective equipment (PPEs) for laboratory workers have also limited adoption of testing in certain patient populations and crimped the nationwide ability to offer convenient, point-of-care testing, which some see as an important component for gauging prevalence and spread of infection.
These commodity products are frequently outsourced from overseas manufacturers and are currently not part of the US emergency stockpiles, Gottlieb said.
Solutions put forth by speakers include greater interchangeability of parts across different manufacturers’ systems, more emphasis on domestic manufacturing of crucial components, and inclusion of these components in national stockpiles of essential medical goods.
Even some of the best resourced, well-connected healthcare systems in the world are struggling with supply chain maintenance. While instrument test systems are in place in her organization, adequate supplies of reagents and swabs and PPEs for lab workers are a challenge, said Elisabeth Nabel, MD, president of Brigham Health, a Boston-based healthcare system, which includes Harvard-affiliated Brigham & Women’s Hospital.
A key example is the widely acknowledged shortage of swabs. The typical US hospital has 10 days of viral swabs on hand on a normal basis, said Soumi Saha, a senior director of advocacy at Premier Inc. At most risk are midsized hospitals, which have on average only a three-day supply on hand of swabs.
The need for swabs increases six-fold over normal usage once Covid-19 patients are admitted to hospitals, she estimated. A survey by Premier conducted between March 16 and 20th found that 23% of the 1,591 hospital members who responded and had Covid-19 positive patients in their facilities reported reagent shortages, and 56% had swab shortages. An estimated 16.3% and 39%, respectively, of those that did not have Covid-19 patients had similar difficulties, she said.
Premier looked at how to increase capacity for viral swabs, including development of interchangeable swabs that could be used across different testing platforms and alternative sampling technologies. Normally, the CDC recommends synthetic fiber that is flossed, with no calcium alginates and no wooden shaft, but the only global manufacturer that meets those requirements is based in Italy and holds patents protecting its technology, she said.
Options for expanding swab availability include flying US military planes to the Italian manufacturer, which is already underway, as those flights are bringing back one million swabs a week, although those have run into distribution issues, she continued. Premier also has looked at how to overcome IP challenges, including several legal pathways that involve use of eminent domain, and declaration of a compulsory license, which is possible because the manufacturer is a federal contractor.
If they can’t resolve these shortages, hospitals will risk going to the gray market, which is a suboptimal solution, she warned.
Diagnostics Manufacturers Ramp Up
The major diagnostics manufacturers have responded to test demand by seeking EUAs for their molecular tests. The first EUA was granted on March 13 to Roche Diagnostics to run on its high-throughput analyzer; another for Hologic Inc. quickly followed.
Thermo Fisher Scientific Inc., which had a US installed base of 200 systems at the start of the pandemic, is also working expanding instrument placement as well as on scaling to produce up to five million test kits per week, said the company’s chief operating officer Mark Stevenson. The FDA has been responsive on these initiatives, as well as being more flexible on allowing solutions for prep materials, and solutions for transport media, he said.
A question for manufacturers is where to distribute supplies, given regional variations in disease surge and need, so that the tests do not sit unused in state or hospital warehouses. Given lack of federal oversight, Thermo Fisher is working with 10 states, focusing most heavily on hot spot regions in New York, New Jersey, and Massachusetts and working with state public health labs on coordination issues, he said. They need to ensure inventory gets where it is needed, and the hospital has capacity to accept it.
One of the first companies to get an EUA for a rapid molecular test was Cepheid Inc. It has 23,000 placements worldwide of its molecular testing point-of-care system GeneXpert, including 5,000 in the US. Those systems can run CLIA-waived respiratory panels in clinics and doctors’ offices, but the rapid SARS-CoV-2 test is currently positioned for patient triage in hospitals, not the outpatient setting, said David Persing, MD, PhD, Chief Medical Officer. Cepheid does not expect to offer that option yet for COVID-19 due to concerns about the infectious nature of the test sample and mixed experiences with self-sampling swabs, he said—challenges that he believes can be overcome down the road. The company is on track to make 20 million cartridges this year for tuberculosis tests but could switch some of that manufacturing to COVID-19 testing.
Roche Diagnostics CEO and President North America, Matt Sause agreed with those challenges and raised questions about ensuring a high-quality chain of custody for point-of-care sampling that ensures proper test formatting. A virus that has an RO (level of contagion) as high as SARS-CoV-2 challenges some of the paradigms around point-of-care testing and guidance from different agencies about keeping healthy people out of hospitals when they are going to be tested, he said. Roche is “looking across the different modalities and evaluating them. It’s very interesting to see how those will be played out in terms of clinical implementation and how they will shape our healthcare.”
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