Just this fall, the U.S. government released its 2022 Biodefense Strategy and Implementation Plan, which set out goals for dealing with future pandemics and other biological threats.
This plan includes strengthening the production and implementation guidelines based on laboratory and point-of-care testing. In the view of some practitioners, these goals are slightly ahead of schedule and too idealistic, but if sufficient attention and investment are given, they are also Sinovac's.
The Biodefense Strategy and Implementation Plan provides guidelines for three categories of diagnostic methods:
- Pathogen diagnostic tests using technologies such as sequencing;
- Specific pathogen tests; and
- Rapid, inexpensive point-of-care testing (point-of-care testing).
For pathogen diagnostic tests, the plan's goal is that in the event of a 'potential domestic or international significant biological event', 'at least one authorized pathogen diagnostic test, such as sequencing, is available at epidemiology relevant locations or deployed within 12 hours, with guaranteed processing of thousands of samples on day one and tens of thousands of samples per day for seven days'.
Meanwhile, specific pathogen tests will arrive in the next wave of testing, within 30 days, in "sufficient quantities" to "support response, containment and control of the incident".
The plan also calls for the development and deployment of point-of-care detection with a runtime of 5 to 30 minutes within 90 days of an incident.
The specific barriers and players vary across these different diagnostic categories, but in each case, technical and implementation improvements are necessary to achieve the government's goals.
"There are some scientific challenges here, there are some organizational challenges, and there are a lot of things that we have to do together, all of which are conceivable and descriptive, but unless the administration and Congress support these things, they won't necessarily happen," said Tom Inglesby, director of the Johns Hopkins Center for Health Security at the Bloomberg School of Public Health.
Inglesby was a senior adviser for testing on the Biden White House's COVID-19 response team. This month, he and several other JHU colleagues, as well as executives from the American Clinical Laboratory Association, published a preprint study that makes recommendations for what they call a "National Diagnostics Action Plan."
At the heart of this plan is the idea that elements of any response need to be in place before the next pandemic level event occurs.
Inglesby said the testing targets set out in the biodefense plan were the right ambition and in line with what the country needed to respond to the earliest COVID in a very different way. And the Biden plan is premised on a really strong partnership between government and industry, which also includes academia and research institutions as part of the diagnostics ecosystem.
However, although the government has tried to quickly bring the different parties together in a timely process, it still cannot come fast enough.
"What we need to do is work ahead of time to prepare for each of these three goals."
Mara Aspinall, professor of practice at Arizona State University's School of Health Solutions and Rockefeller Foundation COVID-19 advisor, also said that while Biden's plan is welcomed, effective implementation will require a lot of additional work and organization.
"It's good to have a baseline plan, and then we need clear leadership and accountability to act quickly if a threat occurs."
According to the biodefense strategy document, the administration aims to develop a more detailed "U.S. Government Diagnostics Joint Capability Plan" under the leadership of the National Security Council and the Office of Science and Technology Policy. A senior government official said the plan is currently being drafted and will be finalized in 2023.
Surveillance of early outbreaks
If the COVID-19 outbreak and other health emergencies are a guide, the state's public health laboratories will play a critical role, especially in the early stages of the response, during which the state should have the capacity to perform pathogen diagnostic testing on thousands of samples on the first day of the event, and tens of thousands of samples per day during the first week, according to the biodefense plan.
The plan does not specify what specific technology should be used, but notes that sequencing is a possibility. Ewa King, chief program officer for the Association of Public Health Laboratories and former laboratory director at the Rhode Island Department of Health, said metagenomic sequencing that can detect new or re-emerging pathogens in a pathogen diagnostic manner is an obvious candidate and an area of growing interest among public health laboratories.
She pointed to wastewater monitoring projects that emerged during the COVID-19 pandemic as an example, noting that these efforts can serve as a springboard for metagenomics moving forward.
King pointed out that although SARS-CoV-2 is a member of the relatively well-studied family of coronaviruses, future outbreaks may be caused by completely novel pathogens and may not be as easy to diagnose quickly.
"When you really don't know what you're looking for, it can take a long time, even months, before you identify a specific pathogen. I think metagenomic sequencing is really about shortening the initial time of identification."
As for how prepared public health labs are to implement this approach, King said that while the technology exists, not every lab currently has access to it.
This will require additional sequencing instrumentation, but perhaps more importantly, many public health laboratories will need to bring in additional bioinformatics expertise given the complexity of analysis of metagenome and data.
However, Inglesby warned against relying too much on public health labs for testing and not relying too much on it over the long term.
"Public health labs are amazing, but they were never intended or funded to be a large-scale diagnostic testing resource. In the early stages of a pandemic when we didn't know what was going on, they were supposed to be a reliable resource that public health officials could rely on. They have a wealth of expertise, but there has been some misunderstanding about what they are supposed to do, and, we There should be no overreliance on a system that is not designed to do ‘mass testing.’”
In fact, at the beginning of the COVID-19 pandemic, the CDC distributed its SARS-CoV-2 molecular tests to state and local health labs, but not to the large private or medical center labs accustomed to doing consumer testing at scale.
During the recent monkeypox outbreak, the United States initially relied on the public health laboratory system for too long before large private labs joined the testing effort. This actually created a delay, because it was discovered early on that the problem was not just scaling up testing sufficiently, but getting results quickly, and nothing was going to happen faster than getting test results into the labs that healthcare providers were used to processing.
Inglesby said that in the case of monkeypox, overreliance on public health laboratories limited the scope of testing because it forced doctors to interact with laboratory systems they were unfamiliar with and didn't know how to navigate.
"They didn't understand that system because they weren't using it every day. In addition to having to get permission from people they normally wouldn't cooperate with, and having to fill out time-consuming paperwork, labs were forced to juggle a new process into their work schedules, so our tests for 'monkeypox' at the beginning of the outbreak were not "Adequate."
Pathogen-specific tests
Despite the disastrous early response of the U.S. government to COVID-19, the rollout of molecular tests for SARS-CoV-2 shows that the government's goal of deploying large numbers of such tests within 30 days of an event is feasible.
On January 21, 2020, CDC confirmed the first domestic case of COVID-19. Two weeks later, the U.S. Department of Health and Human Services declared a public health emergency on February 4. On the same day, the CDC received authorization for its test from the U.S. Food and Drug Administration (FDA) and began distributing it to public health laboratories.
CDC's testing was flawed (due to contamination during production, it turned out), causing it to fail in the hands of some public health labs and significantly delaying its implementation. Still, it provides an example of how quickly targeted molecular tests can be developed.
Of course, scaling up production to a level sufficient to 'support response, containment, and control of pathogens with pandemic potential,' as the biodefense plan states, is a very different issue than producing enough tests for the limited allocation of CDC tests.
In the case of COVID-19, FDA regulations prevented CLIA laboratories from rapidly deploying laboratory-developed tests to detect SARS-CoV-2, which may have limited test availability early in the pandemic. There are also signs that labs are hesitant to invest early in developing such tests. When the FDA relaxed its rules in late February 2020, it expected to see an influx of test reports, but received only seven reports in the first week after the change.
This hesitancy also extends to the in vitro diagnostics industry, as manufacturers face uncertainty on many fronts, including regulatory processes, reimbursement levels and market potential.
Sid, CEO and co-founder of Cambridge, MA-based Proof Diagnostics "We know that there are many companies that are refusing to develop post-COVID, citing the opportunity costs and business risks involved in test development, especially on accelerated timelines," Shenai said.
"If you want to go faster, you need to hire more people, you need to put other projects on hold, and It takes more money.”
Shenai suggested that the federal government could help de-risk the process and incentivize production, for example, by guaranteeing test purchases, although during the COVID-19 pandemic the federal government ultimately did this, but only after manufacturers had begun formally producing the products.
Others have come up with similar ideas. An FDA official interviewed early said that despite the agency's urging, some major infectious disease test manufacturers were initially reluctant to develop SARS-CoV-2 tests because of their experience with previous health emergencies, and the tests they produced ultimately found there was no market.
The official cited South Korea's response to COVID-19 as an example the United States can learn from. Pre-existing relationships and agreements between the South Korean government and diagnostic companies have allowed the country to rapidly scale up production of SARS-CoV-2 tests.
In their preprint, Inglesby and his co-authors similarly recommend that, before the next health emergency, the federal government "establish a series of contractual agreements with a core group of diagnostic manufacturers with proven capabilities to develop and manufacture components, supplies, and test kits at scale" and with "commercial laboratories with national reach and proven expertise in developing tests, facilitating patient sample collection and transportation, maintaining an expert workforce to perform testing, and effectively delivering results across the country."
Key to incentivizing more rapid scale-up of testing for specific pathogens is also to develop procedures that can more quickly determine billing codes and payment rates for these tests. "If we want the private sector to be involved, then we need to get Medicare and Medicaid involved from day one to figure out what the reimbursement codes are," Inglesby said. In addition to putting contracts and reimbursement procedures in place to ensure that commercial vendors and labs can start developing tests and building testing capacity as soon as an emergency is declared, the process of securing and providing clinical samples to test developers to validate their assays needs to be streamlined, as does the regulatory process.
Shenai describes the steps to validate Proof's CRISPR-based COVID-19 test, which has not yet received emergency use authorization from the FDA.
"First, we have to set up testing sites in several states."
"Then we have to get approval from the FDA on important details of the study design and then go through institutional review board review of such a protocol, which takes time to complete."
“Next, you have to create incentives for people to come in and get nasal swabs so that you can get samples. And then you have to validate those samples with comparator reagents, and those reagents themselves are expensive to procure and sometimes you can’t even procure them. All of these things take time.
As such, the National Institutes of Health has launched the Independent Test Assessment Program (ITAP), an example of an initiative that can help speed up the test development process. Launching in fall 2021, ITAP works with test vendors to help them more quickly deliver appropriate A package of submissions is being put together for FDA review.
Inglesby and his preprint collaborators also called for the creation of a permanent public-private partnership to help distribute patient samples to test developers early in the pandemic. ml2
Point-of-care testing for use at the point of care and at home
The 90-day timeline for producing point-of-care tests in the Biodefense Initiative faces many of the same challenges as rapidly ramping up laboratory pathogen-specific testing.
Shenai said: "Such a schedule may be feasible, but there are many factors in the system that hinder rapid development. He hopes that the developers of the diagnostic joint capability program can find a way to reduce these frictions. After all, science and engineering are the fundamental elements of completing the schedule, and not other things."
The 90-day timeline "is feasible given the multiple efforts available," said Jill Heemskerk, deputy director of the National Institute of Biomedical Imaging and Bioengineering and co-lead of the Rapidly Accelerated Diagnostics (RADx Tech) initiative.
RADx Tech is a $1.5 billion grant to develop and implement a variety of COVID-19 tests. |
“This is a challenging but achievable goal, and we must give 120% of our efforts to achieve this goal. ”
First point-of-care test during COVID-19 pandemic, Cepheid’s Xpert Xpress The SARS-CoV-2 test, which received an EUA from the FDA exactly two months after the first cases were detected in the United States and approximately six weeks after HHS declared a public health emergency, demonstrates that molecular point-of-care tests can be developed well within the timeframes set by government plans.
point-of-care testing for home use is a different issue, and the first EUA for this test will arrive in December 2020. Scaling up the production of point-of-care tests for home use is also a challenge, and accessibility remains an issue well into 2021.
As with laboratory testing, market and regulatory uncertainty has made some companies, including major IVD manufacturers, wary of entering the U.S. home testing market, This suggests that here, the federal government's -guaranteed purchase agreement and efforts to clarify and streamline the regulatory process may be necessary to advance inspection development and production.
Regarding the latter point, Heemskerk said ITAP has proven to be very popular among both test vendors and the FDA, with some stakeholders advocating for the program to be expanded to other diagnostic methods. The program is expanding the program to multiplexed COVID-19, influenza and RSV testing.
“The FDA has been a very enthusiastic partner, and under the ITAP framework, NIH helps vendors generate the exact data that the FDA wants, in the templates they want, to the standards they want, working with a trusted partner. It reduces all the time spent going back and forth with the company. This is why all regulatory time lags occur.
RADx also announced up to $300 million in new funding for the development and commercialization of home and point-of-care COVID-19 tests. In this tender, Heemskerk said, the program emphasizes tests that can quickly adapt to new pathogens. test platform. It also focuses on scalability and cost, considerations that have not been as important in previous RADx efforts.
"Especially on the molecular side, we need to find a way to make the technology simpler, more robust, more standardized and routine, so that production can be scaled up and costs reduced." "
" What's also critical is maintaining the relationships RADx and NIH have with the FDA and other government agencies that have allowed us to develop a good communication model on COVID that we can now pivot to very quickly. ”
Securing funding for non-COVID-19 work has also been a challenge, as much of the program’s funding is earmarked for COVID-19 work, it has had to pull funding from other sources to support recent monkeypox work.
"We want to have a funding mechanism that is a solid foundation that can be used for any pathogen so that when new threats emerge we can take immediate action without having to go through a new contract process and find new funding."
The 'bottom line' to achieve the goal
The government plan provides a framework to address testing in the event of another pandemic or health emergency, but Inglesby noted that sustained focus, political commitment and funding are key to putting it into action. He expressed doubts that those elements are currently in place.
" He said: "There's not a lot of involvement from Congress, and that's not a good thing.
Congress is expected to include the PREVENT Pandemics Act into a year-end omnibus bill, but while some provisions of the bill could improve government coordination on pandemic planning and, Inglesby said, "really try to raise the profile" of pandemic preparedness efforts, it does not provide any additional funding for those efforts.
The Biden administration has requested $10 billion in supplemental funding for pandemic preparedness, but the money is unlikely to make it into the omnibus budget. In March, Congress cut $15.6 billion in COVID-19 funding from previous spending bills, which was already well below the $30 billion the administration originally requested.
Congress must next year reauthorize the Pandemic and All-Hazards Preparedness Act (PAHPA), which authorizes budget levels and establishes the framework for many of the nation's pandemic preparedness and response activities and programs, including the Biomedical Advanced Research and Development Authority (BARDA).
Inglesby said the reauthorization process could focus Congress's attention on pandemic preparedness more generally, although he noted that the bill is not a funding bill and therefore does not address any funding challenges.
"We need to do the work ahead of time to prepare for each of these test goals, and they all require different types of problem solving. Although I would say it is unlikely that there is money in the budget right now to actually achieve these three goals."
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original link (English):
https://www.360dx.com/covid-19/white-house-covid-dx-goals-potentially-feasible-more-funding-coordination-needed-experts#.Y6Okk3ZBwfk
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