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RADx Revved up COVID Testing Development. Will It Also Change the US Dx Ecosystem? Part 2

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Part 2 of two stories. The RADx program has been critical in getting COVID-19 diagnostic tests to the public during the pandemic. Along with numerous success stories, though, some firms stumbled in spite of RADx's guidance. Part 1 of this series explored the goals of the program and what it offered its awardees. In part 2, the series also looks at some of the obstacles that other firms faced even with RADx's help. 

NEW YORK – The Rapid Acceleration of Diagnostics, or RADx, program was created by the US National Institutes of Health to help propel diagnostic tests for COVID-19 onto the market at the start of the pandemic when few tests were available and demand was near desperate.

Overall, while members of the NIH and RADx say that the program has met or even exceeded expectations, it has also made a few investments that might be viewed as missteps in hindsight. Most notably, some participants in the program received tens of millions of dollars yet appear to have little to show for the money they spent at the public's expense.

That said, there is no obvious recipe for commercial success in diagnostics, and the space from bench to bedside has been called the valley of death for a reason: Many innovative, novel technologies never make it out of the lab or stumble on the hurdles of real-world users, manufacturing scale-up, and distribution.

The RADx team expended every effort to help each member of its portfolio and will continue to do so, Bruce Tromberg, director of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), said. Nevertheless, some of the award recipients have not yet been able to reach all the milestones that RADx set, while others met the funding milestones only to subsequently falter.

Obtaining regulatory clearance in the form of Emergency Use Authorization from the US Food and Drug Administration was a bar RADx set for most of the award recipients, admittedly a lower regulatory bar than the typical full approval or clearance.

Through a thorough examination of public documents, it appears that seven of the technologies RADx supported in Phase II funding have not yet secured an EUA. These include tests from Mologic, Palogen, Salignostics, Tangen Biosciences, Anavasi Diagnostics, and AvantGen, as well as the Savanna platform from QuidelOrtho. 

These are primarily novel approaches from mostly smaller firms, excluding QuidelOrtho, and it appears that some of the EUA non-issuances may be related to changes in SARS-CoV-2 viral prevalence colliding with supply chain issues. Tromberg also noted that the priority level for different types of testing evolved with the pandemic and that obtaining EUA opened up additional funding levels so these firms may not have received the full amount of the initial award.

While RADx awarded QuidelOrtho $70.5 million to scale its Sofia rapid antigen test, it separately also awarded the firm $717,800 to support development of an over-the-counter flu and COVID test as well as a respiratory viral panel on its Savanna molecular diagnostic system.

On a recent call with investors, QuidelOrtho's management said the company has been waiting on Savanna's EUA for so long, it is considering pivoting to the 510(k) pathway. And, the shortage of microprocessors has meant fewer Savanna instruments can be built, so for the current respiratory season the firm is now directing those systems to the European Union, where Savanna is CE marked and fully commercialized.

The microprocessor shortage seems to have impacted other firms in the portfolio, too. RADx awarded Anavasi Diagnostics $14.9 million for a low-cost, handheld molecular diagnostic test called Ascencio. The firm previously said that, like much of the industry, it struggled with microprocessor supply chain issues, despite the fact that its system was purpose-built to use only a single, simple chip. Anavasi submitted its EUA in March 2022 but is still awaiting authorization.

Tangen Biosciences is another example of a small novel device maker in the RADx portfolio that seems to have struggled. RADx awarded the Branford, Connecticut-based startup $3 million to scale its portable, low-cost, multiplexed lab-on-a-disc molecular diagnostic system. The company also received support from the US Department of Health and Human Services' Biomedical Advanced Research and Development Authority, or BARDA, in April 2020 and four months later it closed an approximately $12 million Series B financing and leased commercial space, but it still has not obtained EUA for a COVID-19 test. Tangen did not respond to requests for comment.

Another RADx fundee that has yet to obtain an EUA is Bedford, UK-based Mologic, which was awarded $11.8 million, in part to scale up manufacturing of a CE- marked COVID-19 rapid antigen test. The firm was subsequently acquired for $41 million by a group of investors led by the Soros Economic Development Fund, with support from the Bill & Melinda Gates Foundation. Now a nonprofit called Global Access Diagnostics, it introduced its Covios rapid antigen test in September 2021 but has not obtained an EUA.

While RADx provided mentoring and consultations for these firms, final decisions about whether or how to market their technologies were left to companies, according to Todd Merchak, co-program lead for the RADx-Tech subprogram created to spur development of at-home, point-of-care, and lab-based testing.

"We tell them what we think is the right path, but at the end of the day we can't make them do something," Merchak said. And, while the decisions of less seasoned management teams might account for some of the commercial failures, "the challenge they faced was having to do all these things so quickly and not having previous experience going through these processes," he said.

Another challenge was "constantly evolving market dynamics," Merchak said. "Because COVID has been cyclical, there are times when you can't make enough tests and times where nobody wants them at all," he said. This inability to predict consumer demand months in advance makes it "extremely challenging for manufacturers to adequately respond," he said. 

Other startups and small firms RADx supported obtained EUA but have not yet seen significant sales of their tests.

Merchak noted that for a startup company without experience it could take between two and four years to iron out the kinks that come along with high-scale, high-volume manufacturing. The RADx team was able to get many of its fledgling firms to what might be considered a reasonable scale of production in normal times, he said. Scaling from that point, however, is another mountain to climb, involving building new assembly lines and hiring manufacturing staff.

"It is a really hard thing to do, to go from a company that sells no products to a company that sells hundreds of thousands of products — it usually takes years, and we got it down to about a year or less," he said.

Similarly, waves of evolving viral variants also hit some firms' technologies harder than others. RADx awarded Meridian Biosciences approximately $8 million for multiplex panels on its RevoGene system and it obtained EUA in November 2021. The Cincinnati-based firm then delayed RevoGene's launch when it discovered that the test could not detect the Omicron variant. Meridian is being acquired by Korean diagnostic company SD Biosensor and investment firm SJL Partners for $1.5 billion, and the RevoGene test was reauthorized by the FDA later that month.

Other firms obtained EUA for their novel technologies but appear to have struggled on the business end.

Fluidigm was awarded $34 million from RADx for a high-complexity saliva-based RT-PCR test, and the firm's stock rose nearly 30 percent when it announced it had obtained an EUA in August 2020. It subsequently got an EUA for a swab-based assay in February 2022. But any lift provided by its COVID-19 testing has faded. Now named Standard Bio Tools, the firm's net losses tripled this year from a year ago and it entered a restructuring process that it said includes de-emphasizing its COVID-19 diagnostic testing products.

Australia-based Ellume, meanwhile, has reportedly entered voluntary administration, a process similar to Chapter 11 bankruptcy in the US. RADx had awarded the firm $30 million for its rapid antigen test, followed by $3.5 million for a combination flu/COVID test.

At the end of 2020, Ellume received the first EUA for an OTC COVID-19 test and opened a flagship US manufacturing plant in Frederick, Maryland, in March 2021. Eight months later, it recalled 2.2 million tests due to a potential for false-positive results.

Passionate about all the novel technologies in the portfolio, Tromberg described the Ellume quantum dot and integrated electronic technology as "beautiful," but noted that the product experienced one of the hazards associated with being first to market.

"Who knew there would be a billion $3 rapid antigen tests that followed their $30 price point test," he said, adding that the case will likely be taught in business schools someday.

RADx is still working with Ellume to try to figure out their best path forward, Tromberg said, noting that the technology is uniquely amenable for use by people with accessibility issues and is currently being provided to them for free by the US government.

Other firms' struggles may have been related to the lack of precedent for their technologies.

RADx's Merchak noted that, in general, rapid antigen tests are an established technology with established manufacturing capacity, while point-of-care molecular tests tend to be more complex with potentially more supply chain risk. "The ability to scale manufacturing adequately is a bottleneck of that technology," he said.

One example of this might be Talis Biomedical, a Redwood City, California-based firm that RADx awarded $25.4 million to scale its point-of-care Talis One system and develop a multiplex high-throughput version.

Talis went public in early 2021 but saw its stock price plummet from $16 per share to $.77 per share within 18 months. In August, Talis asked the FDA to revoke its EUA, according to a US Federal Register document. That month, the firm also announced that it would cut a third of its workforce and stop investing in the commercialization of its COVID-19 assay, in part due to manufacturing issues and invalid rates greater than 10 percent. The firm has said it will, instead, pivot to developing tests for women's health and sexually transmitted infection testing.

Talis declined a request for comment, but its website currently states: "The Talis One Test System is not authorized, cleared, or approved by the FDA and is not available for sale."

Tromberg said that RADx attempted to help Talis in every way possible, even using the Defense Production Act to help the company secure a part it needed for manufacturing its test. But, in the end companies are more than their technologies, he said.

Private firms in the RADx portfolio have also struggled to achieve success, though the reasons are less transparent.

South Korea-based Palogen was awarded $8 million for an RNA biosensor to detect COVID, and the firm's website describes two products. It has not obtained EUA, and it is unclear if, or where, its tests are for sale. RADx awarded Jerusalem, Israel-based Salignostics $6.5 million for an innovative direct-from-saliva-sample COVID test, and the firm recently secured $8 million in Series A financing. The test does not have EUA but does appear to be commercialized outside of the US.

Other RADx investments yielded products that may have never been used, ones that were different than what was originally funded, and ones that were never mentioned publicly by the firms that got the awards.

For example, Madison, Wisconsin-based Flambeau Diagnostics was founded in 2020 with $12 million from RADx. The startup set out to develop a lab-in-a-van test system called RapidX, which uses proprietary sample prep and robotics to achieve a throughput of 1,000 tests per eight-hour shift. The firm collaborated with the Yale SalivaDirect program, but it is unclear if any of the mobile testing units were ever actually deployed. 

RADx also awarded Santa Clara, California-based Xtrava $6.2 million for a rapid antigen testing platform that was meant to have "10 to 100 times throughput improvement," according to the RADx website. However, when the firm obtained EUA in October 2021 for a test, the instructions for use indicate it is a basic, single-use home test.

And, South San Francisco-based synthetic DNA firm Twist Bioscience was awarded $6.8 million to develop a 10-minute OTC and point-of-care lateral flow immunoassay, according to the RADx website. Twist was granted an EUA for a next-generation sequencing-based test in 2021. The company does not appear to have publicly mentioned the RADx award, and on its recent fiscal 2022 results call, executives described a new factory in Oregon but did not clearly mention diagnostics on the list of initial products to be manufactured there. 

None of the companies above responded to requests for comments.

Steve Schachter, a member of the RADx team who oversaw rollout of the program, said in an interview that, in the end, some of the technologies simply did not work to the standards that the FDA set. "We tried and tried with some of the companies to make their performance better, and there are any number of reasons [that they didn't work], but it wasn't for lack of effort on our part," he said.

RADx's Tromberg concurred. "We fought very hard for every company," he said.

'An ant learning to dance with an elephant'

RADx's dedication proved more fruitful for other firms, particularly smaller, privately held ones, and startups, for whom the program was a crash course in entrepreneurship that many described as transformational.

In all, about one third of the Phase II RADx awards went to novel devices from small firms or startups whose technologies were awarded an aggregate of approximately $200 million.

For example, RADx awarded Ubiquitome $2.5 million to support development of its Liberty16 mobile PCR system, helping to rapidly transform the New Zealand-based instrument maker from a developer of research-use-only thermal cyclers to a player in the clinical diagnostics space, according to the firm's CEO Paul Pickering.

For a small company, working with a massive US federal agency sometimes felt like "an ant learning to dance with an elephant," Pickering said, particularly given the time pressure exerted by the out-of-control global pandemic.

Nevertheless, Ubiquitome enjoyed prioritized access to the FDA, support from experienced regulatory and quality control resources, collaboration with the RADx Test Verification Core, and assistance with supply chain challenges. The firm secured EUA in a collaboration with Yale's SalivaDirect initiative and has since seen uptake in on-site workplace surveillance testing, Pickering said, adding that a recent pilot study showed the test has 100 percent concordance with central lab results.

Similarly, Mammoth Biosciences found the "vision and support" provided by RADx to be "instrumental" in advancing its CRISPR-based assay, according to the firm's CEO Trevor Martin. RADx awarded Mammoth approximately $23.1 million for its DETECTR COVID test, he confirmed, and helped the firm with clinical specimen acquisition, clinical validation, submissions to and interactions with the FDA, supply chain issues, and bioinformatics.

The guidance that RADx provided to firms that were new to the commercialization process also proved crucial in helping them get their tests and platforms to market.

Peter Lee, VP of strategic and corporate development at MicroGem, said that his firm's experience with RADx accelerated its commercialization stage by several years. RADx awarded the Charlottesville, Virginia-based company $50.7 million for its Sal6830 Point of Care PCR System, and the firm obtained EUA in June 2022.

MicroGem acquired New Hampshire-based Jump Start Manufacturing in 2021 and opened a large-scale test kit production facility in Ogden, Utah. It also established a US-based supply chain and expanded its production capacity to 4 million COVID-19 tests per month. Lee noted that MicroGem is now positioned to pivot its platform to other pathogens as part of its overarching mission to "democratize equitable access to testing" for underserved and hard-to-reach people.

Meanwhile, MatMaCorp received $4.6 million from RADx to build out its Solas 8 PCR system. Phil Kozera, CEO of the Lincoln, Nebraska-based firm, said MatMaCorp was assigned a team of industry veterans and government liaisons to guide it through the process of assay development, scaling, and regulatory submission, with continuously updated objectives provided via video meetings each Monday.

From its original niche of "penside" testing in agricultural markets, MatMaCorp had always intended to enter the bedside testing space, particularly to help populations in rural areas. Kozera said the firm was able to go from early development stages to an EUA in six months, which "would not have been possible without guidance from the RADx team." MatMaCorp subsequently took the knowledge it gleaned from RADx and developed a handheld PCR system called My Real-Time Analyzer, or Myrta, for which "early clinical testing is very encouraging," Kozera said. 

RADx's relationship with the FDA was also beneficial for some firms, including Uh-Oh Labs. "The guidance on the regulatory process was particularly important, as RADx experts had a direct line with the FDA and helped relay the changing regulatory landscape," said Alex Jiao, president and chief business officer of the Santa Clara, California-based firm. Without RADx support, Jiao said, Uh-Oh Labs would likely not have been able to obtain EUA and sell products in the volumes it does today.

RADx awarded Uh-Oh Labs $14.9 million for an isothermal molecular diagnostic system called Loop-de-Loop and provided introductions to quality, financing, operations, and commercialization consultants, Jiao said. RADx continues to provide regulatory support for new products, he added, including an OTC, at-home COVID test in development.

According to Teresa Abraham, Visby Medical's VP of scientific and tech partnerships, the RADx program was "a great success story in how the government can rapidly support diagnostic development, manufacturing, and procurement at a scale that was only previously seen in the vaccine space."

The San Jose, California-based company received $9.6 million from RADx for its single-use PCR device, which Visby deployed to transition from manual to automated manufacturing. RADx also helped solve a supply chain issue related to swabs and reagents, Abraham said. Visby was subsequently awarded $25.5 million from BARDA to develop an at-home COVID and influenza test and has described its intention to pivot to STI testing. The FDA granted the firm's request to revoke its EUA earlier this month.

Lastly, Dave Kelso, president and CEO at Minute Molecular, estimated in an interview that RADx support of his firm's Diagnostic Analyzer for Specific Hybridization (DASH) system compressed 15 years of commercial efforts down to approximately two years.

Minute Molecular obtained an EUA in March for its at-home molecular test and expects to launch soon. The Evanston, Illinois-based company has met the milestones for $17 million of its $21.3 million RADx award so far, Kelso said, and in his opinion RADx is a great new model for federal funding as it seems likely to lead to better healthcare outcomes through improved diagnostics.

In separate interviews, executives representing the novel device makers PathogenDx, Detect, Mesa Biotech, Qorvo Biotechnologies, and Clip Health — awarded approximately $110 million in aggregate — also described the RADx support as transformational, emphasizing that the regulatory and manufacturing expertise in particular accelerated commercialization and likely altered the trajectories of their companies.

RADx's future

As the pandemic evolved, the RADx team continued to expand its support of test development, validation, and commercialization. It sponsored a variant task force to assess performance of at-home tests and recently opened a third and final development funnel, in part aimed at developing assays that are more accessible to people with disabilities. Tromberg said that 160 applications came in for that and are now entering the deep dive process.

In the end, the NIBIB has spent approximately $1.7 billion in administering the RADx-Tech and RADx Advanced Technology Platforms, or RADx-ATP, programs, according to a spokesperson.

And, although some pieces of the portfolio were more successful than others, MicroGem's Lee contrasted RADx with Operation Warp Speed, an effort by the federal government to develop COVID-19 vaccines and noted that $12.4 billion was invested in multiple vaccine development programs with the full understanding that not all projects would result in safe and effective jabs.

Medical historian Harvey Fineberg has described RADx as a success, too, with "far reaching lessons" for medical technology development.

"The selection funnel process fostered by RADx accelerates the transition from discovery to product," he wrote last year in Issues in Science and Technology, adding that the program offers "a model for future science aimed at any definable and desired health outcome" and lessons that should be applied to the proposed $6.5 billion Advanced Research Projects Agency for Health.

As the pandemic lurches toward becoming an endemic, the future for some of the novel technologies in the RADx portfolio remains unclear. Still, "we feel pretty good about the process we put in place and the outcomes that can be achieved," RADx's Merchak said.

Now, "we are trying to leverage the lessons from COVID and all the technology and innovation to continue the evolution towards more home-based and point-of-care diagnostics," he added.

In assessing the overall success of RADx, Tromberg cited the aphorism "a rising tide lifts all boats," noting that RADx's investments may have helped the overall diagnostics industry.

This might be particularly true for the adoption of decentralized testing, including point-of-care and home-use tests for infectious diseases. For example, firms like Co-Diagnostics and Sense Biodetection have leaned into the home testing space, while technologies like an at-home molecular assay for sexually transmitted infections from Lucira were likely accelerated in this new environment.

Keeping the home-based testing market sustainable will be a future challenge, but Tromberg sees the pandemic-accelerated shift to telemedicine as enabling this transition, including for multiplexed at-home tests, for which Tromberg said, "the future is bright."

Although the digital health surveillance piece remains a challenge, Merchak said that with newer therapeutics, the test-to-treat paradigm is a promising way to reduce spread of infectious disease. Tromberg noted that RADx is now working with the Administration for Strategic Preparedness and Response (ASPR) to validate in-home treatment processes following at-home testing.

Overall, in terms of OTC, at-home molecular diagnostics, "the revolution is here; it is just a matter of sustaining it," Merchak said. Once the emergency goes away, the EUA platforms will need to be transitioned to 510(k) clearance with the FDA, but, "once we get the first one or two OTC molecular tests, that opens the flood gates," he added.

RADx also continues its work on platforms for digital reporting through its Mobile Application Reporting through Standards, or MARS program, and it has branched into supporting rapid variant genotyping tests in collaboration with Thermo Fisher Scientific, Helix, and Rosalind.

The RADx program seems to have also benefited the diagnostics ecosystem in other ways that may reverberate into the future.

Tromberg noted that throughout the process each application has been treated carefully, with deep dive applicants in particular benefiting from feedback even if their project wasn't funded. The team also established a "redirect program" to send promising proposals to other institutes or funding opportunities, like the NIH SEED program.

Continuing the closer relationship RADx has forged between the NIH and FDA in the future might also help to satisfy one of the recommendations from HHS's Office of the Inspector General that the FDA work with federal partners like the NIH and Centers for Disease Control and Prevention to establish a program — akin to the Independent Test Assessment Program (ITAP) or the Test Verification Core (TVC) — that conducts all the assay validation for EUA applications during an emergency, rather than requiring each individual company to do so.

Regarding ITAP and the TVC, "every manufacturer would like to go through this process," Tromberg surmised, but at the moment there is not enough funding. In the meantime, "we can create tools that can be disseminated and shared with everyone," enabling an easier transition from an FDA template to an institutional review board protocol, for example.

In fact, Tromberg emphasized that RADx is "engageable and approachable," and very keen on sharing the processes it put in place. The team has also tried to "RADx-ify" other programs in the NIH and has multiple funding funnels now ongoing, he said.

In September, RADx-Tech launched an $8 million effort to support diagnostics aimed at improving maternal health by prioritizing at-home, point-of-care, and wearable technologies. A collaboration with other NIH institutes, the program will use the RADx strategies like a funnel of evaluation, deep dive assessments across a variety of parameters, mentoring, and milestone-based support. RADx is also collaborating with other institutes on a funding solicitation through its Blueprint MedTech program to support commercial technology focused on diagnosis and treatment of neurological disease, and it has helped initiate a funding opportunity in point-of-care HIV viral load testing.

Going forward, Tromberg said RADx will also continue to provide in-kind support for its portfolio as long as possible. Although the funding is ending for the RADx program, Tromberg said the diagnostics industry has a voice, and can speak to the FDA, for example, or lobby Congress.

"The industry knows quite well where bottlenecks are, where de-risking has to occur, where accelerated authorization could be beneficial," he said. "The partnership potential with our RADx community is enormous, and the challenge for us is to figure out ways to make it sustainable at some level."

Schachter noted that, because in many ways RADx's approach was so new, "undoubtedly there are ways it could be improved." That said, the fact that RADx processes have now become embedded into other NIH initiatives means it may one day become the standard format that translational medtech research is supported.

"By any metric, I think it was productive and successful," Schachter said. Despite the pandemic, and the impact it had on the many hundreds of people who pitched in to the RADx effort, "it was a very special and unusual effort," he said. "Hopefully, we've laid the foundation for an approach that can be scaled up even quicker next time."