The first reports of an unusual cluster of pneumonia cases in the city of Wuhan, China,
emerged in December 2019, heralding a global pandemic. As of July 13, 2020, more than
3.3 million U.S. residents have received a diagnosis of coronavirus disease 2019 (Covid-19),
and more than 135,000 have died.
Of great concern are the data showing the disproportionate effect of Covid-19 on ethnic
and racial minorities.
Since January 2020, the National Institutes of Health (NIH) has been involved in multiple
wide-ranging collaborative efforts spanning the development of vaccines and diagnostic
strategies, the identification and evaluation of safe and effective treatments, the
understanding of the natural history of the disease, and the study of racial and ethnic
In this article, we describe the additional role of the NIH in the effort to increase
the range and availability of diagnostic tests for the causative virus, SARS-CoV-2
(severe acute respiratory syndrome coronavirus 2).
We begin with a review of current and projected testing capacity needs and review
different types of diagnostic tests. We then describe the Rapid Acceleration of Diagnostics
(RADx) program, its goals, and its focus on underserved populations. As will become
clear, this program represents a dramatic extension of the usual NIH mode of supporting
research. RADx was established in just a few days; it covers the entire life cycle
of the target technologies; it is tightly focused on timelines and outcomes; it receives
applications primarily from small companies; it is partnering with other agencies
such as the Office of the Assistant Secretary for Health, the Biomedical Advanced
Research and Development Authority (BARDA), and the Department of Defense; and it
is expressly focused on health disparities. We describe here the four components of
RADx and their goals, and we end with a review of the challenges ahead.
On April 24, 2020, Congress appropriated $1.5 billion, from the $25 billion provided
in the Paycheck Protection Program and Health Care Enhancement Act for SARS-CoV-2
testing, to the NIH. Within 5 days after the legislation was signed into law, the
NIH launched RADx to support the development, production scale-up, and deployment
of accurate, rapid tests across the country. From a timing perspective, the RADx initiative
was conceived by Congress to provide near-term solutions to increase the number of
tests available by the fall of 2020, as schools and universities evaluate the safety
of in-person classes and as the annual influenza season begins. In the slightly longer
term, RADx also aims to support the development and production of innovative diagnostic
technologies as well as strategies for making testing available to diverse, vulnerable,
and underserved populations through 2021. One of the goals of the RADx initiative
is to expand capacity so that by December 2020, approximately 2% of the U.S. population
(6 million persons) can be tested per day, with more tests ready for rapid deployment
in proportion to national demand.
Current Testing Capacity and Projections
In the week leading up to July 13, 2020, daily diagnostic testing capacity in the
United States was fluctuating between 520,000 and 823,000 tests.
Models that provide robust estimates of the number of tests needed per day vary widely.
Some experts estimated that 900,000 tests per day would be needed in May.
Others forecasted the need for 5 million tests per day by June, increasing to 20 million
tests per day by July.
Although national totals are helpful benchmarks, the models must account for a range
of variables, including different levels of regional prevalence and community spread,
the needs of high-risk communities (e.g., nursing homes, shelters, prisons, and factories),
and the frequencies and types of testing to be conducted. For example, the type and
characteristics of a test that are required will differ when testing is conducted
to determine personal infection status as compared with evaluating population-level
surveillance. Test performance (the limit of detection, sensitivity, specificity,
and the positive predictive value), turnaround time, cost, accessibility, and acceptance
are critical factors in a successful testing strategy that can meet the needs of individual
persons and communities across the country.
Types of Diagnostic Tests
Current diagnosis of acute SARS-CoV-2 infection relies on tests that detect either
viral RNA or viral antigens.
Most existing methods for Covid-19 testing use reverse-transcriptase–polymerase-chain-reaction
(RT-PCR) tests that detect nucleic acid sequences specific to SARS-CoV-2. These tests
are highly sensitive and specific when conducted in centralized laboratories with
standardized protocols, but they require a large amount of laboratory space, complex
equipment, regulatory approvals for the laboratory operations, and skilled laboratory
leadership and technicians. Results generally take time to become available, with
windows ranging from hours to days, and the need for transport of specimens to a central
laboratory leads to further delays. For this reason, low-complexity molecular diagnostic
point-of-care tests with rapid turnaround have substantial practical advantages.
A number of point-of-care tests have now received Emergency Use Authorization (EUA)
by the Food and Drug Administration (FDA).
Antigen tests work by detecting the presence of viral proteins and can provide rapid
results, similar to the way pregnancy tests operate.
Antigen tests can offer fast and scalable point-of-care performance, but they have
lower sensitivity than most nucleic acid–based assays.
This limitation can be a concern in high-risk settings such as nursing homes, where
missing the detection of an infected person can lead to serious consequences. Although
a number of manufacturers are known to be developing antigen-based tests, to date
only two have received an FDA EUA.
Serologic tests that detect antibody response are also being developed by numerous
companies, but these tests are not suitable for the diagnosis of acute infection,
since human antibodies are not formed until 2 to 3 weeks after viral infection. Thus,
their primary use is to document previous exposure to the virus.
The development and scaling of serologic tests are not under the auspices of the NIH
Components of the RADx Program
The RADx program has four components. RADx-tech aims to identify, accelerate the development
of, scale up, and deploy innovative point-of-care technologies as early as the fall
of 2020. RADx–Advanced Technology Platforms (RADx-ATP) will support the scale-up of
somewhat more advanced technologies that can achieve immediate, substantial increases
in capacity. RADx-rad (shorthand for radical) will focus on truly nontraditional approaches
for testing that have a slightly longer horizon. RADx–Underserved Populations (RADx-UP)
will establish community-engaged implementation projects to improve access to testing
in underserved and vulnerable populations.
Leveraging Our Scientific Creativity — RADx-tech
The RADx-tech program offers extensive expertise and support to bring the diagnostic
technologies that require additional clinical, regulatory, and commercialization assistance
from development to deployment. The RADx-tech program uses a rigorous, rapid-review
process that provides independent evaluation of the technology and the potential to
scale. The program leverages the long-standing Point-of-Care Technology Research Network
(POCTRN), which is run by the National Institute of Biomedical Imaging and Bioengineering.
In a process based on an “innovation funnel,” applications move rapidly through multiple
review gates that involve increasing selection pressure (Figure 1).
On entering the innovation funnel, each project is evaluated by a team with wide-ranging
expertise. Projects that are deemed to be promising enter into to a weeklong intensive
review process, which we refer to as a “shark tank” or “deep dive.”
In phase 0, multiple expert reviewers provide a detailed assessment of the technology
and give critical feedback to the NIH and the project teams. Approximately 15 to 20%
of completed RADx-tech applications enter phase 0. For those projects that are successful
(25 to 30% of phase 0 projects), detailed, milestone-driven work packages are developed
in order for projects to enter phase 1. Technologies are then rigorously tested and
validated in the independent POCTRN validation core over a monthlong process to ensure
that these new tests meet or exceed their predicted analytic performance. If a project
is judged to be successful at that point, rapid scale-up and clinical testing in phase
2 gets under way, with substantial financial assistance provided.
Applications that have been received to date by the RADx-tech program span nearly
every stage of technology development, with submissions coming from small and midsize
companies, academic laboratories, early-stage start-up companies, and large commercial
manufacturers (Figure 2). It is not uncommon for applicants to still be preparing
for their EUA submission to the FDA. Promising technologies that have been reviewed
by the program include innovations that allow high-throughput, portable, and point-of-care
platforms, from CRISPR (clustered regularly interspaced short palindromic repeats)
technologies for the detection of viral nucleic acids to lateral flow strips for both
nucleic acid and viral antigen testing.
Many platforms integrate advanced microfluidic components and state-of the-art readout
strategies that use compact optics and electronics. Overall performance, ease of use,
and digital reporting are facilitated by smartphone systems that are designed for
nonexperts. In addition, alternatives to conventional nasopharyngeal and anterior
nasal swab sampling are being explored,
and a majority of prototypes involve the use of saliva, oral swabs, and other collection
sites (Figure 3).
As of July 13, 2020, a total of 2587 expressions of interest have been received, and
more than 600 full applications have been submitted from 41 U.S. states and the District
of Columbia. Within 8 weeks after the launch, 27 projects had successfully made it
through the shark tank to phase 1, and the entry of the first project into phase 2
is imminent. As technologies and companies go through this process, the RADx program
is also seeking to identify testing platforms that may be especially suitable for
testing small groups or isolated, underserved populations at point-of-care sites or
in rural or remote areas that do not have access to high-throughput robotic testing
systems. Technologies that reduce the facility footprint, decrease overall testing
complexity, and provide rapid results will be especially helpful, and the program
will work to assist in the deployment of these systems in these specialized environments.
As part of this process, ease of use, including specimen-collection methods and clear
and easy-to-understand instructions to facilitate widespread uptake, will be integrated
into the process.
Active collaborations with other government agencies are critical during this process.
The NIH is closely coordinating with the Office of the Assistant Secretary for Health,
BARDA, and Department of Defense to ensure that each party is aware of the discussions
and existing relationships taking place with private-sector companies, to ensure no
duplication of funding, to streamline communications, and to leverage the experience,
knowledge, and technical capacities of different agencies within the government.
Achieving Short-Term, Rapid Scale-up — RADx-ATP
Not all emerging technologies need the shark tank approach. As shown in Figure 1,
a bypass pathway is also provided to catalyze the rapid development of technologies
that are already at a more advanced stage of development. The RADx–Advanced Technologies
Platforms (RADx-ATP) program provides a rapid-response application process for companies
with an existing point-of-care technology that has already been authorized by the
FDA for the detection of SARS-CoV-2 and that has the ability to scale production to
between 20,000 and 100,000 tests per day by the fall of 2020. In addition, the company
must have infrastructure and a deployment or placement strategy that enables tests
to be made rapidly available in point-of-care settings. Companies are asked to develop
a robust plan to collect data continuously to support a submission to the FDA for
a Premarket Approval (PMA) or a Premarket Notification (510[k]).
The RADx-ATP program is also seeking to expand high-throughput laboratories (also
called “mega-labs”) that are in a position to increase testing capacity to 100,000
to 250,000 tests per day. These laboratories have been certified according to the
Clinical Laboratory Improvement Amendments regulations and are already in operation
with the necessary equipment and trained staff to guarantee a test-turnaround time
of 24 hours (from the time that the sample is obtained to the availability of the
result). Such high-throughput laboratories generally have the equipment to analyze
large numbers of tests with well-developed automated workflows to process samples
and obtain results rapidly. Newer technologies, such as next-generation sequencing,
can read out hundreds to thousands of genes or gene regions simultaneously
and should be able to support large-scale, population-level testing for surveillance
purposes, possibly on the order of millions per day.
Pooling strategies are also being considered for population-level surveillance, because
they can greatly increase throughput when testing resources are limited.
If a pooled test result is negative, then the patients who provided the samples are
considered to be negative for active SARS-CoV-2 infection. If a pooled test result
is positive, then each sample from the pool of patients needs to be tested individually.
The efficiency of pooling has been shown to depend on the prevalence of SARS-CoV-2,
test sensitivity, and patient-pool size and will need further evaluation before widespread
Molecular bar-coding is another promising approach. In the first step, the individual
sample is labeled with a DNA tag, in order for it to be identifiable at the molecular
level. Massive pooling can then be done to increase the number of tests that can be
processed at once. Positive samples can be identified by their unique tag, but the
pooling step can greatly decrease the use of reagents, equipment, and labor.
This approach may even allow for a range of other viral pathogens to be detected during
the same analysis.
Looking Further Ahead — RADx-rad
Not all technologies will be ready for near-term production scale-up and deployment.
A special component of the program (RADx-rad) has been established to evaluate the
usability, access, robustness, or accuracy of a wide range of nontraditional technologies
or new settings (e.g., home-based testing technologies) for the detection of SARS-CoV-2
infections. Projects under the RADx-rad component will be focused not just on the
development of new technologies or approaches but also on the novel repurposing of
existing technologies. Furthermore, RADx-rad will support those innovative technologies
that are on a more extended timescale and that will take longer to develop than a
6-month time frame. Such technologies include, for example, the use of biologic or
physiological biomarkers to detect an infection or predict the severity of disease,
including the likelihood of the multisystem inflammatory syndrome in children,
or the use of chemosensory changes as an early indicator of viral positivity.
Other examples include the use of biosensors to detect the presence of the virus in
or the analysis of wastewater to conduct community-based surveillance.
Focus on Underserved Populations — RADx-UP
It is clear that racial and ethnic minorities are bearing a higher burden of disease
and mortality from Covid-19.
In particular, non-Hispanic Blacks, Hispanics, and American Indians and Alaska Natives
are hospitalized and die at disproportionately higher rates than other groups.
This disproportionate burden in health outcomes for underserved populations and racial
and ethnic minorities shines a bright light on long-standing health disparities in
the United States and is of profound concern.
The goal of this part of the RADx program (RADx-UP) is to understand factors that
have led to the disproportionate burden of the pandemic on underserved populations
and to support improved access and uptake of SARS-CoV-2 testing. The program aims
to examine infection patterns and efforts in order to increase access to and effectiveness
of testing methods by building an infrastructure that can be leveraged for the ongoing
Covid-19 public health efforts, especially as the impending influenza season begins
in the fall. Through engagement with communities and in close alignment with their
leaders, a series of interlinked, pragmatic implementation science projects at multiple
sites across the country are being planned to investigate, in real time, the effective
approaches to testing within these populations. In addition, in order to be responsive
to the communities that this initiative will partner with and to understand more clearly
the multitude of factors influencing the ability and willingness of a group to be
tested for SARS-CoV-2, the program is obtaining strong guidance on social, ethical,
and behavioral issues by means of the establishment of a research program focused
solely on these issues.
The NIH has been engaged almost continuously in battling epidemic diseases over the
past several decades. From human immunodeficiency virus (HIV) infection to influenza,
SARS, Middle East respiratory syndrome (MERS), Ebola, and Zika, each pandemic brings
its own idiosyncratic issues that require unique solutions. We anticipate that challenges
to the RADx program are likely to arise on several fronts. First, on the technical
side, many promising prototypes under consideration are in the early proof-of-concept
stage. It is likely that many will fail along the way. Much effort will be needed
to conduct clinical validation rapidly and to obtain regulatory authorizations and
approvals. Access to clinical samples for clinical validation has already emerged
as an issue that is impeding progress for companies.
Another challenge will be to identify digital health platforms that provide connectivity
among test results, electronic health records, and public health organizations. Many
smaller diagnostic companies do not have expertise in this area, and it will be important
to ensure their access to this expertise in the planning stages. Data should be able
to be transmitted to the patient and health care provider and to state and local public
health authorities with the use of national interoperability standards and common
data elements to collect key demographic, test result, and clinical outcome information.
This will lay the foundation for the future point-of-care clinical practice and research
enterprise in the years to come, in which deidentified, privacy-protected, patient-level
test data can be linked to clinical outcomes to form curated, analyzable data sets.
Second, on the manufacturing side, scaling up of production is a complex enterprise
that involves a wide range of factors, from ensuring sufficient supplies of swabs,
raw materials, reagents, and equipment to establishing new production lines and manufacturing
facilities within aggressive timelines. These are likely to be logistic feats that
will require rapid access to capital, equipment, and skilled staff.
Third, on the distribution side, once increased testing capacity is available, managing
the distribution and implementation of tests into the appropriate venues and geographic
localities will be critical. We anticipate coordinating closely with Operation Warp
and leveraging the logistic expertise of the Department of Defense. Uptake of testing
may also be an issue.
All these challenges are being addressed with unprecedented levels of coordination
and collaboration across academia, government, industry, and nonprofit foundations.
We anticipate that these interactions will substantially affect traditional barriers
and facilitate the first burst of increased testing capacity by the fall of 2020.
Expanding the capacity, throughput, speed of returning results, analytic performance,
and regional placement of diagnostic technologies is urgently needed and, if successful,
will contribute importantly to the current national efforts to curb the Covid-19 pandemic
and help to reduce inequities for underserved populations. As we embark on this initiative,
the challenges ahead are considerable, and the timetable is truly daunting. Aiming
to achieve this rapid evaluation, validation, and scale-up has rarely, if ever, been
attempted at this pace. However, the NIH is in a position to serve as a “venture investment”
organization and is currently striving to operate in that entrepreneurial spirit.
The success of the RADx program will depend on truly innovative ideas coming forward
from the minds and laboratories of technology developers, a robust and rapidly responsive
expert evaluation system, extensive collaborations in validation and scale-up with
experts from all sectors, and strong community partnerships to support testing availability
and uptake. All these partners are profoundly energized by a sense of urgency, opportunity,
and responsibility to provide testing at scale in the face of this global pandemic.