NEW YORK – The National Institutes of Health's Rapid Acceleration of Diagnostics team has closed the submission process and earmarked $1.2 billion to support SARS-CoV-2 diagnostics from more than 40 labs and companies.
The final RADx portfolio of products to be developed and scaled includes a diversity of diagnostics from companies such as Illumina, Quidel, Fluidigm, and Mesa Biotech, and is likely to result in a near-term manufacturing boom in rapid antigen tests and over-the-counter home-use diagnostics.
Funded through congressional appropriations and other RADx sources, the overall effort was coordinated by the RADx Tech and Advanced Technology Platforms (ATP) wings. These are part of the NIH's National Institute of Biomedical Imaging and Bioengineering under the broader umbrella of the US Department of Health and Human Services. The RADx Tech program specifically is implemented by the Point of Care Technologies Research Network, or POCTRN.
Todd Merchak, co-program lead for the RADxTech program who has also been involved with POCTRN for many years, said in an interview that home-use SARS-CoV-2 diagnostic tests were a goal for RADx from the outset.
RADx Tech/ATP received more than 700 full applications for support since launching the program in April, Merchak said, and the final portfolio now has approximately 40 companies and labs. RADx does not disclose the projects until they reach a Phase 2 contract stage, but a total of 27 Phase 2 contracts have been awarded so far.
As described in a New England Journal of Medicine special report in July, the RADx team and its collaborators intended to assemble a diverse testing portfolio, including different types of lab-based assays as well as point-of-care and over-the-counter tests.
And, in addition to the 700 applications, Merchak said RADx teams reached out to companies large and small that did not directly apply, and all applicants went through a rigorous evaluation of their technology and management teams.
Because of all this, he personally believes that the complete RADx portfolio represents the most promising available technologies to help the US face the pandemic.
Approximately half of the total appropriated funds have now been dispersed with the remainder dedicated primarily to milestone-gated payments, Merchak said.
Specifically, $520 million has been awarded in Phase 2 contracts for late state development and scale up — with seven awards announced in July, nine in September, and six in October, for example — but additional funds were already used on solicitation and review, validation, clinical studies, implementation, and operational infrastructure, as well as early funding awards to selected companies and labs.
The program undertook a full evaluation of what would be needed for the pandemic from a testing perspective in March of 2020, Merchak said. The team assessed everything, "from lab-based testing, to point-of-care testing, to over-the-counter at home," as well as the different setting and disease prevalence scenarios that impact which type of test is most useful.
Merchak said RADx's plan when the program launched in April was to start by scaling lab-based RT-PCR and other mature, established technologies, then accelerating point-of-care and rapid antigen tests as they were developed.
"Our goal from the outset was to get at-home testing in the style of a pregnancy test in every home at some point in 2021," Merchak said, adding, "We are on target for that right now."
The publicly disclosed portfolio includes three manufacturers of sample collection and preparation materials — Ceres Nanosciences, Oasis Diagnostics, and Yukon Medical— and three instrument makers — Ubiquitome, MatMaCorp, and Flambeau Diagnostics — but is otherwise heavily weighted towards diagnostics developers.
It includes seven antigen test developers and 14 developers of high- or low-throughput molecular tests for labs or the point of care.
Among antigen test developers, one from Quanterix is described as lab-based but the remainder could potentially be for use at the point of care, or even for home use.
Specifically, there are five tests with direct potential for home use, from GenBody, ANP Technologies, Luminostics, Ellume, and Maxim Biomedical. A sixth test, from Quidel, requires a reader, although the firm has recently described the possibility of selling readers for consumers to maintain and use in the home.
Before the pandemic, this latter idea may have seemed far off if not impossible, but to Merchak, the pandemic has just accelerated this inevitable outcome.
For pandemic control, "It was clear to us from the beginning that you need rapid testing, period, even it if it less sensitive or less accurate," he said, adding that the RADx team and its collaborators are now gathering data to show that serial antigen testing can be on par with a single lab-based PCR test.
Unlike molecular diagnostics, antigen tests can be manufactured at very high levels, are less expensive, and have faster turnaround times, which will make them "the key to our response in the next few months here," Merchak said.
A test from Australian diagnostics developer Ellume is the furthest along so far, having already obtained EUA and becoming the first over-the-counter at-home rapid SARS-CoV-2 antigen test. Merchak said RADx expects a few more to be authorized for home use in "hopefully in the next month or so."
The RADx program awarded Ellume nearly $30 million in Phase 2 funding. This month, Ellume was also awarded an additional $232 million in support from HHS and the Department of Defense to scale up manufacturing.
The 14 molecular assays that RADx is supporting include sequencing assays from Illumina, Helix, and Ginkgo Bioworks.
There are also high-throughput kits and systems — from the likes of Aegis Sciences, the Broad Institute, PathGroup, Sonic Healthcare, and Fluidigm — as well as low-throughput or single-use nucleic acid amplification tests from Meridian Biosciences, MicroGEM International, Mesa Biotech, Talis Biomedical, and Visby Medical, and one CRISPR-based test from Mammoth Biosciences. The low-throughput molecular tests may also have the potential for point-of-care use.
Among the 27 Phase 2 projects, those from Illumina and Ginkgo Bioworks are currently deemed "inactive." A representative at NIBIB said that this could mean they had reached the end of their performance period, or that they have been terminated, but added that the agency will not be publicly disclosing why the contracts were ended.
An end in sight?
Parallelization has been the key to the accelerated one-year scale-up timeline, Merchak said.
"Under normal circumstances, if you are an investor like the NIH or a venture capitalist, and you are funding a project ... you typically have milestones that are set up serially," he said. For example, full chemistry optimization in a wet lab would then lead to the next step of building a device, followed by clinical validation and advancing through the US Food and Drug Administration regulatory process.
Typically, it takes on average about five years to get a new diagnostic to market, Merchak said, and most rapid infectious disease tests are used seasonally, so manufacturers have never before had to scale above producing a few thousand per day.
Now, the US needs millions of tests per day, and is asking manufacturers to scale to producing 100,000 or more units daily. "It is unprecedented," Merchak said.
So, RADx has encouraged developers to create assays at the same time as cartridges, doing any possible performance studies simultaneously, while also lining up the regulatory path and building up the manufacturing capacity and supply chain.
Design-locked products are validated with live virus by a third-party design lab at Emory University. Then, the project moves to Phase 2, which typically involves support of more than $20 million, but by this point will have all partners and vendors lined up, and can simply "press 'Go,'" Merchak said.
This ambitious approach has paid off. "We have an at-home test in under six months," Merchak said referring to Ellume. "We are doing something that has never been done before," he added.
This progress has been made possible through the dedication of a large team of consultants who spent careers in all the different domain areas of in vitro diagnostics, Merchak said. These include specialists in assay design, microfluidics engineering, and clinical and infectious disease medicine. There are also regulatory experts on the team who help with RADx's weekly meetings with the Food and Drug Administration, and manufacturing experts "who know how to take a product with no assembly lines and build a fully automated facility in under 12 months."
Merchak noted that investments in early-stage technologies are inherently risky, but that the domain experts have been very thorough in their assessments, and, "There are no unknowns — we uncovered every part of the process to understand exactly where the fail points might be."
While there has been ongoing criticism of the US testing response, Merchak noted that scaling up development and manufacturing of novel assays simply takes time.
Indeed, the former coordinator of the US COVID-19 testing efforts for HHS, Brett Giroir, noted in a presentation at the American Association for Clincal Chemistry virtual meeting in December that, essentially, money has not been the issue, as the US has invested more than $4.5 billion in testing.
Merchak concurred. "There are inherently laws of physics that can't be bent or broken," he said, particularly with manufacturing scale-up to such tremendous levels. It take about one year to build and fully validate a diagnostics device assembly line. "That is ultimately the rate-limiting step to do millions of tests per day. It just takes time, there is no shortcut there."
Furthermore, antigen tests are "finicky," Merchak said, and must be made foolproof so that they can be reliably used by an average American who is testing herself at the kitchen table or over the bathroom sink.
That said, the at-home infectious disease testing concept has been brewing and evolving for more than 13 years through POCTRN and its network of five technology hubs, Merchak said, and POCTRN support was instrumental in the development of point-of-care diagnostic systems like the Binx io and Hemex Gazelle, for example.
Now, "We see the RADx initiative as accelerating putting more tests into the hands of a patient," Merchak said, noting that the platforms it is supporting are also likely to be leveraged for other infectious disease testing.
The pandemic has now enabled the last leg of the process, he said.
"You can design tests, you can build them, you can manufacture them, but somebody has got to buy them and there has got to be a market for them," Merchak said. The pandemic specifically has accelerated the clinical adoption, as clinicians and the public will likely be more open to using these types of tests. That will benefit the public, but will also help the POCTRN program to continue to move these types of tests forward in the future.
What this will mean for the practice of healthcare remains to be seen, and some infectious disease experts and clinical microbiologists have been wary of decentralized molecular testing and home antigen testing in the past. However, the pandemic also seems to have accelerated telehealth, and perhaps a clinician on a video chat could help guide patients to accurately perform and read assays.
The Quidel proposal of potentially having Sofia immunoassay readers in a patient's home, with infectious disease test cartridges available in pharmacies, did not strike Merchak as far-fetched.
"It is totally reasonable," he said. "I've been in the weeds on this for over a decade, so to me this was all going to happen inevitably," he said. At the same time, "If I take my NIH hat off ... it is a big shift, but I think it is a positive one for sure. That reader at home, you can put any cartridge in it for any number of different diseases."Â Â
Overall, Merchak said the last year has been a whirlwind, but that the US is dealing with an unprecedented problem.
"Everybody obviously wants the pandemic to be over yesterday, and we are working as hard as we can," he said. "I think we are in a good spot, and more testing is coming online every month. We'll get there." Merchak anticipates enough tests available in the next few months "to really make an impact" on K through 12 programs in particular, but also, "hopefully getting folks back to work and out and about."