NEW YORK – This fall the Biden administration released its 2022 Biodefense Strategy and Implementation Plan, laying out its goals for responding to future pandemics and other biological threats.
The plan includes benchmarks for ramping up laboratory-based and point-of-need test production and implementation, setting targets that, according to a number of industry stakeholders, are at the moment largely aspirational but could become feasible given sufficient attention and investment.
The Biodefense plan provides benchmarks for three categories of diagnostics: pathogen-agnostic tests using technologies like sequencing, pathogen-specific tests, and rapid, inexpensive, point-of-need tests.
For pathogen-agnostic testing, the plan's goal is to have "at least one authorized pathogen-agnostic test, such as sequencing, for use in epidemiologically relevant locations, or for deployment within 12 hours, for thousands of samples on the first day, and tens of thousands of samples per day within seven days" of a "potential nationally or internationally significant biological incident."
Meanwhile, pathogen-specific tests will arrive in the next wave of testing, within 30 days and in "sufficient quantities" to "support the response to, and containment and control of" an incident.
The plan also calls for the development and deployment of point-of-need tests with run times of between five and 30 minutes within 90 days of an incident.
The specific hurdles and parties involved vary across these different diagnostic categories, but in each case, improvements in technology and implementation will be necessary to meet the administration's goals.
"There are some science [challenges], there are some organizational challenges," said Tom Inglesby, director of the Johns Hopkins Center for Health Security at the Bloomberg School of Public Health. "We have to do many things together, all of which are imaginable and describable, but they aren't necessarily going to happen unless there is support for them both in the administration and" in Congress.
Inglesby was formerly senior adviser for testing on the Biden White House's COVID-19 Response Team. This month, he and several other JHU colleagues, along with executives at the American Clinical Laboratory Association, published a preprint study putting forth their proposal for what they called a national diagnostics action plan.
At the core of their plan is the notion that the elements of any response need to be put in place well before the next pandemic-level event.
The testing goals set out in the Biodefense plan are "the right level of ambition and are consistent with what the country needs to respond in a very different way than it did to COVID in the earliest days," Inglesby said.
The Biden plan, he added, is "predicated on there being a really strong partnership between government and industry that also includes academia and research institutions that are part of the diagnostic ecosystem." However, he said, though the government has tried to bring the different parties together quickly in a "just-in-time process," it still doesn't happen fast enough.
"What we need to do is work ahead of time to prepare for each of these three goals," Inglesby said.
Mara Aspinall, professor of practice at the Arizona State University College of Health Solutions and adviser to the Rockefeller Foundation on COVID-19, likewise said that while the Biden plan was welcome, effective implementation would require significant additional work and organization.
"Having a baseline plan is great," she said. "Then we need clear leadership and accountability to move quickly once a threat happens."
According to the Biodefense strategy document, the administration aims to develop a more detailed "US Government diagnostics joint capabilities plan" led by the National Security Council and the Office of Science and Technology Policy. A senior administration official said that it is currently drafting this plan and will finalize it in 2023.
The initial response
If the COVID-19 outbreak and other health emergencies are a guide, the nation's public health labs will play a key role, especially in the early days of the response, during which, according to the Biodefense plan, the country should be capable of performing pathogen-agnostic testing on thousands of samples within the first day of an incident and tens of thousands of samples per day within the first week.
The plan does not specify what particular technology should be used but indicates sequencing as one possibility. Ewa King, chief program officer at the Association of Public Health Laboratories and the former laboratory director for the Rhode Island Department of Health, said that metagenomic sequencing capable of detecting novel or reemerging pathogens in a pathogen-agnostic way is an obvious candidate and an area of increasing interest with public health labs.
She cited the wastewater surveillance programs that arose during the COVID-19 pandemic as an example of efforts that could "serve as a springboard for metagenomics going forward."
King noted that while SARS-CoV-2 was a member of the relatively well-studied coronavirus family, future outbreaks could be caused by pathogens that are "completely novel and which might not be quite so easy to diagnose quickly."
"When you really don't know what you are looking for, it could be a long time — months — before a specific etiological agent is determined," she said. "I think [metagenomic sequencing] is really to shorten that initial time for recognition."
As for how well prepared public health labs are to implement such approaches, King said that while "the technologies exist … they aren't really available in every lab at the moment."
Additional sequencing instrumentation would be required but, perhaps more importantly, many public health labs would need to bring aboard more bioinformatic expertise given the complexity of metagenomic data analysis, King said.
Inglesby cautioned, however, against relying too heavily or too long on public health laboratories for testing.
"Public health labs are amazing, but they were never intended or funded to be mass diagnostic testing resources," he said. "They are supposed to be resources for public health officials and for the earliest moments of a pandemic where we don't know what is happening. They have a lot of expertise, but there has been kind of a misunderstanding of what they are supposed to do and an overreliance on a system that wasn't intended to do" mass testing.
Indeed, at the beginning of the COVID-19 pandemic, the US Centers for Disease Control and Prevention distributed its SARS-CoV-2 molecular test to state and local health labs but not to large private or medical center labs accustomed to doing consumer testing at large scale.
Inglesby said that during the recent monkeypox outbreak, the country again relied for too long on the public health laboratory system before bringing large private labs aboard the testing effort. He said that the issue isn't just one of scaling testing sufficiently but also of quickly getting testing into labs that healthcare providers are accustomed to dealing with.
In the case of monkeypox, overreliance on public health labs limited the reach of testing by forcing doctors to interact with a lab system they weren't familiar with and didn't know how to navigate, Inglesby said.
"They didn't understand that system because they don't use it every day," he said. Along with having to get permissions from people they don't normally work with and having to fill out time-consuming paperwork, the labs were forced to handle a new process in their work schedules, "and so we were way undertesting [for monkeypox] at the start" of the outbreak.
Disastrous though it was, the rollout of molecular testing for SARS-CoV-2 suggests that the administration's goal of deploying large quantities of such tests within 30 days of an incident is doable. The CDC confirmed the first domestic case of COVID-19 on Jan. 21, 2020. Two weeks later, the US Department of Health and Human Services declared a public health emergency on Feb. 4. That same day, the CDC received US Food and Drug Administration authorization for its test and began distributing it to public health laboratories.
The CDC test was flawed (due, it turned out, to contamination during the production process), causing it to fail in the hands of some public health laboratories and significantly delaying its implementation. Nonetheless, it provides an example of just how quickly a targeted molecular test can be developed.
Of course, scaling production to levels sufficient to, as the Biodefence plan specifies, "support the response to, and containment and control of" a pathogen with pandemic potential, is a much different matter than producing enough assays for the limited distribution intended for the CDC test.
In the case of COVID-19, FDA regulations that prevented CLIA labs from quickly deploying laboratory-developed tests to detect SARS-CoV-2 likely limited availability of testing early in the pandemic. There were also indications that labs were hesitant to invest in developing such assays early on. When the FDA loosened its regulations at the end of February 2020, it expected to see a large influx of test submissions but instead received just seven submissions in the first week following the change.
The hesitancy extended to the in vitro diagnostic industry, as well, as manufacturers confronted uncertainty along a number of fronts including with regulatory processes, reimbursement levels, and market potential.
"There are numerous companies that we know of that refused to go after COVID," said Sid Shenai, CEO and cofounder of Cambridge, Massachusetts-based Proof Diagnostics, citing the opportunity costs and business risks involved in test development, especially on an accelerated timeline.
"If you want to move faster, you'll need to hire more people, you'll need to put other projects on hold, and that requires more money," he said.
Shenai suggested that the federal government could help de-risk the process and incentivize production by, for instance, guaranteeing test purchases — something that it ultimately did during the COVID-19 pandemic, but only after it was well underway.
Others have recommended similar notions. In an earlier interview with 360Dx, an FDA official said that despite the agency's urging, a number of major infectious disease test manufacturers were initially reluctant to develop SARS-CoV-2 tests because of their experiences during previous health emergencies where they had produced tests only to find there wasn't ultimately a market for them.
The official cited South Korea's COVID-19 response as an example the US could learn from. Preexisting relationships and agreements between the South Korean government and diagnostics firms allowed the country to rapidly scale up SARS-CoV-2 test production.
In their preprint, Inglesby and his coauthors likewise recommended that prior to the next health emergency, the federal government "establish a series of contractual agreements with a core group of diagnostic manufacturers with a proven capacity to develop and manufacture components, supplies, and test kits at scale" as well as with "commercial laboratories that have national reach and demonstrated expertise in developing tests, facilitating patient sample collection and transport, maintaining an expert workforce to perform tests, and efficiently delivering results at national scale."
Also key to incentivizing more rapid scale-up of pathogen-specific testing will be developing processes for more quickly establishing billing codes and payment rates for these tests, Inglesby said. "We need to get [Centers for Medicare and Medicaid Services] involved from the first day to figure out what the reimbursement codes will be if we want the private sector to be involved."
Beyond the matter of putting contracts and reimbursement processes in place to ensure commercial vendors and labs begin developing tests and building out test capacity immediately upon a declaration of an emergency, the process of securing and providing clinical samples to test developers for validating their assays needs to be streamlined, Inglesby said, as does the regulatory process.
Shenai described the steps involved in validating Proof's CRISPR-based COVID-19 test, which has not yet received Emergency Use Authorization from the FDA.
First, testing locations had to be set up in several states. Then, "we had to gain agreement from the FDA on important details of the study design, then go through [Institutional Review Board] review of such protocols, which take time to do properly," he said. "Then you have to create incentives for people to come in and get their noses swabbed so you can get the samples. Then you have to validate those samples with comparator assays that are themselves expensive to procure — and sometimes you can't even procure them. All of these things take time."
Inglesby highlighted the National Institutes of Health's Independent Test Assessment Program (ITAP) as an example of the kind of initiative that could help speed the test development process. Launched in the fall of 2021, ITAP worked with test vendors to help them more quickly put together appropriate submission packages for FDA review.
Inglesby and his preprint coauthors also called for a permanent public-private "testing coordinating body" to, among other things, help allocate patient samples to test developers early in a pandemic.
Point-of-need and home testing
The Biodefense plan's 90-day timeline for the production of point-of-need tests faces many of the same challenges involved in rapidly ramping up lab-based pathogen-specific testing.
Such a timeline is potentially doable, "but there are frictions in the system right now to moving fast," Shenai said, adding he hopes that the developers of the diagnostics joint capabilities plan will find a way to reduce those frictions and that "the science and the engineering are the drivers of the timeline and not anything else," he said.
The 90-day timeline is "feasible provided multiple kinds of efforts," said Jill Heemskerk, deputy director of the National Institute of Biomedical Imaging and Bioengineering and co-lead of the Rapid Acceleration of Diagnostics (RADx Tech) program, which has led a $1.5 billion effort to develop and implement a variety of COVID-19 tests. "That's the whole point. It was meant to be an aspirational but achievable goal and something for us to work toward."
During the COVID-19 pandemic, the first point-of-care test — Cepheid's Xpert Xpress SARS-CoV-2 assay — received FDA EUA exactly two months after the first case was detected in the US and roughly six weeks after HHS declared a public health emergency, indicating that molecular point-of-care assays can be developed well within the timeline set by the administration's plan.
Home tests were a different matter, with the first EUA for such an assay coming in December 2020. Scaling up production of home tests was also a challenge, with accessibility remaining a problem well into 2021.
As with lab-based tests, market and regulatory uncertainty made a number of companies, including major IVD manufacturers, wary of wading into the US home testing market, suggesting that here, too, guaranteed purchase agreements from the federal government and efforts to clarify and streamline the regulatory process may be necessary to drive test development and production.
Regarding the latter point, Heemskerk said that ITAP has proved highly popular with both test vendors and the FDA, with a number of stakeholders advocating expansion of the program to other diagnostics. The program is expanding the program to multiplexed COVID-19, flu, and RSV tests.
"FDA has been an extremely enthusiastic partner," she said. Under ITAP, NIH helps vendors "generate the exact data [FDA] wants, in the template they want, to the standards they want, with a trusted partner. It takes away all that time that gets spent going back and forth with companies. That's where all the regulatory time lag comes in."
RADx has also announced up to $300 million in new funding for the development and commercialization of home and point-of-care COVID-19 tests. Heemskerk said that in this solicitation the program is emphasizing testing platforms that can adapt quickly to new pathogens. It is also focused on scalability and cost, considerations that she said were not as central to previous RADx efforts.
"We're trying to really develop new technologies that can bring lab quality results to point-of-care and home tests," she said, noting that particularly on the molecular side, "we need to find a way to make the technology simpler, more robust, and more standardized and routine so that manufacturing can scale up and be less expensive."
Equally key, Heemskerk said, is maintaining RADx's and NIH's relationships with the FDA and other government agencies "that have gotten us to a point with COVID where we can turn on a dime very quickly now."
Securing funding for non-COVID-19 efforts is also a challenge, she said, noting that because most of the program's funds are earmarked for COVID-19 work, it had to pull funding from other sources to support recent monkeypox work.
"We'd like to have funding mechanisms in place that are kind of a warm base that can be used for any pathogen so that when a new threat emerges we are ready to act on it right away and don't have to go through a new contracting process and find new funds," she said.
The bottom line
The administration plan offers a framework for addressing testing in the case of another pandemic or health emergency, but Inglesby noted, sustained attention, political commitment, and funding are essential for putting it into action. He expressed doubts as to whether those elements are currently in place.
"There isn't a lot of engagement on the congressional side, which is not good," he said.
Congress is expected to include the Prepare for and Respond to Existing Viruses, Emerging New Threats, and Pandemics Act (PREVENT Pandemics Act) in the end-of-year omnibus, but while this bill has certain provisions that could improve government coordination around pandemic planning and, Inglesby said, "does try to raise the profile of" pandemic prep, it doesn't provide any additional funding for such efforts.
The Biden administration has asked for $10 billion in supplemental funding for pandemic preparation, but that money is unlikely to make it into the omnibus. In March, Congress cut $15.6 billion in COVID-19 funding from the previous spending bill, which was already well short of the $30 billion the administration had initially requested.
Next year Congress must reauthorize the Pandemic and All-Hazards Preparedness Act (PAHPA), which authorizes budget levels and establishes the framework for many of the country's pandemic prep and response activities as well as for programs including the Biomedical Advanced Research and Development Authority (BARDA). The reauthorization process will likely bring congressional attention to questions of pandemic preparedness more generally, Inglesby said, though he noted that the bill is not a funding bill and, so, can't address any funding challenges.
"We need to do work ahead of time to prepare for each of these [testing goals], which are each going to require different kinds of problem solving," he said. "Though I would say that it is unlikely that there is funding in the budget right now to truly meet these three goals."