There has never been so much concerted global focus on IVDs. And with good reason, as IVDs have always proved essential to detect infectious disease threats and steer treatment and resources. This is true with the current crisis, even if it is the lack of COVID-19 diagnostics that has come to the fore. How to scale up the diagnostic testing, and why testing took so long to appear are not only questions in healthcare but on the nightly news. A nation, it seems, is now familiar with PCR and nasopharyngeal swabs.
Unusual but not unwarranted. In many volumes of our global IVD market reports, we have suggested there is not enough testing broadly for the disease threats the world faces. Kalorama Information has covered IVD markets for two decades, including the market of greatest relevance to COVID-19 diagnostics, molecular testing. Our World Market for Molecular Diagnostics is now in its 8th Edition. Molecular testing is particularly useful with a viral threat: RT- PCR can accurately detect the the presence of viral DNA. The molecular diagnostics segment is the fastest growing segment within the global IVD market, at $8,760 million in 2019.
- Non-COVID-19 Test Volume Down. Quest Diagnostics filed a form 8-K in which it noted that during the last two weeks of March volume declined by more than 40 percent. “in March, the Company experienced, and anticipates it will continue to experience, a material decline in testing volumes due to the COVID-19 pandemic…this has lead to a significant reduction in physician office visits, and also the cancellation of elective medical procedures, customers closing or severely curtailing their operations (voluntarily or in response to government orders), and the adoption of work-from-home or shelter-in-place policies, all of which have had, and we believe will continue to have, an impact on the Company’s operating results” Thermo Fisher also reported a strong Q1 but poor volume last two weeks of March.
- Eurofins and OrthoClincal Diagnostics announced joint plans to develop a high-throughput anti-body test. https://www.fiercebiotech.com/medtech/ortho-eurofins-lay-out-plans-for-high-throughput-covid-19-antibody-blood-testing from Fierce: “This would allow centralized, lab-based diagnostic hardware to process blood samples at scale, screening patients for previous infections and possible immunity in volumes similar to how molecular testing machines check swabs for active signs of the novel coronavirus.”
- They join 50 other developers who have notified FDA – https://www.fda.gov/medical-devices/emergency-situations-medical-devices/faqs-diagnostic-testing-sars-cov-
- Handheld Test Ships: Mesa Biotech announced it is shipping 10,000 of its handheld Accula SARS-CoV-2 molecular rapid point of care (POC) tests this week. The company’s COVID-19 test uses patented technology to enable ‘near patient’ testing outside of the central laboratory with diagnostic results in 30 minutes.
- Federal Watchdog Blames Lack of Testing: A recent report from the Office of the Inspector General pins the lack of testing as a factor in the severity of the outbreak by limiting hospital containment, patient isolation and resource allocation of masks and PPE “Hospitals reported that severe shortages of testing supplies and extended waits for test results limited hospitals’ ability to monitor the health of patients and staff. Hospitals reported that they were unable to keep up with COVID-19 testing demands because they lacked complete kits and/or the individual components and supplies needed to complete tests. Additionally, hospitals reported frequently waiting 7 days or longer for test results. When patient stays were extended while awaiting COVID-19 diagnostic test results, this strained bed availability, personal protective equipment (PPE) supplies, and staffing.” https://oig.hhs.gov/oei/reports/oei-06-20-00300.pdf
- Cellex Gets Antibody Nod: The U.S. Food and Drug Administration (FDA) has granted the first emergency use authorization for a test to determine COVID-19 status from antibodies in blood samples to the biotechnology company Cellex. The immunoglobulin G/immunoglobulin M (IgG/IgM) rapid test can detect antibodies against SARS-CoV-2 in serum, plasma, or venipuncture whole blood. Healthcare providers can use the test for individuals with suspected cases of COVID-19, the FDA noted in a letter to the company about the authorization. To use the test, professionals first must allow the device cassette, specimen, and buffer solution to equilibrate to room temperature. A 10-µL specimen can then be transferred to the center of the sample well. Once the sample well is free of liquid, professionals add two sample diluent drops, and the results can be read 15 to 20 minutes later. Cellex’s headquarters are in Research Triangle Park, NC, and the company maintains an Asian base in Guangdong, China.
- U.S. Deaths Could Be Undercounted – Repors that not all deaths are being counted, even where patient had been PCRed positive and coroners requesting COVID-19 tests for autopsies being denied: https://www.nytimes.com/2020/04/05/us/coronavirus-deaths-undercount.html
- Now, a Worry About HAIs: Hospital infections were already a concern, and obviously overcrowded conditions are a bad situation for their continued spread. As hospitals deal with COVID-19, the threat of MRSA and other HAIs is also a concern. A Lancet study of 41 hospitalized coronavirus patients, 10% developed secondary infections. A different Lancet study of 99 COVID-19 patients with secondary infections identified five types of bacteria in their systems. One of these was antibiotic-resistant. In a 2016 study, CDC experts found that overall rates of antibiotic use in U.S. hospitals did not change from 2006-2012. More than half of patients received at least one antibiotic during their hospital stay. However, there were significant changes in the types of antibiotics prescribed with the most powerful antibiotics being used more often than others. There was a 37 percent rise in the use of carbapenems.
Ventilator-associated pneumonia (VAP) is one of the most frequent ICU-acquired infections and one to watch now.
- Infections caused by bacteria that develop resistance to carbapenems can be especially hard to treat, and even deadly. There was also a 32 percent rise in the use of vancomycin, an important antibiotic used to treat common antibiotic-resistant infections caused by methicillin-resistant Staphyloccus aureus, or MRSA. Every patient in the first Lancet study, even those without secondary infections, received antibiotics. Ventilator-associated pneumonia (VAP) is one of the most frequent ICU-acquired infections and one to watch now. Reported incidences vary widely from 5 to 40% depending on the setting and diagnostic criteria. VAP is associated with prolonged duration of mechanical ventilation and ICU stay. The estimated attributable mortality of VAP is around 10%, with higher mortality rates in surgical ICU patients and in patients with mid-range severity scores at admission. First Light Diagnostics is combating antibiotic resistance by shortening targeted therapy decisions to be made in hours versus several days using their current technology, MultiPath™ First Light CEO, David Macdonald, will be hosting a webinar tomorrow, Thursday, April 2nd at 3:00 pm EST to discuss their new rapid test. I’ve included the rsvp link for your convenience: First Light Webinar with the company’s CEO David Macdonald: Thursday, April 2 at 3:00 pm EST https://www.forcefamilyoffice.com/event-details/force-webinar-first-light-diagnostics
- Detection is Only One Component of Testing: Blood gas testing is often required for ventilator-assisted patients and those undergoing evaluation for respiratory distress, providing insights into a patient’s oxygenation level. Siemens Healthineers announced a new RAPIDPoint 500e Blood Gas Analyzer he RAPIDPoint 500e Blood gas testing plays a critical role in managing infected patients and monitoring their respiratory distress. Routine blood gas testing is also performed when patients require mechanical ventilation, providing the status of a patient’s oxygenation levels and enable healthcare providers to determine whether adjustments to ventilator settings or other treatments are required. Abbott’s iSTAT is a market leader in rapid blood gas testing. d-Dimer has been cited as a factor in coronavirus survival in a Lancet study: d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. https://www.ncbi.nlm.nih.gov/pubmed/32166607 The study also cites C-Reactive protein (CRP) as a risk factor. In high levels CRP has been associated in negative outcomes in studies of COVID-19 patients in China. https://www.medrxiv.org/content/10.1101/2020.02.23.20026963v1 and https://www.ncbi.nlm.nih.gov/pubmed/32166607
- Throughput Arrives: On the large-scale test side, the impact of models like the Roche cobas 6600 or the Abbott m2000 can be seen in the increased testing at major labs. Commercial labs such as LabCorp and Quest — and some hospitals and academic medical centers — have been making their own tests available and are ramping up testing capacity quickly. Quest said it is now conducting 25,000 tests per day in the U.S., which it plans to expand to 30,000 by the end of this week. At the same time, Cepheid has shipped POC tests. Time will tell the impact of those in the field, but we’d expect increased case numbers as these systems can be available where a provider and patient is and provide a 45 minute result. No special operator training is required. NeuMoDx™ SARS-CoV-2 Assay, the NeuMoDx Systems integrate the entire process of testing for SARS-CoV-2 – from specimen lysis through detection or ‘sample to result” – and provide operators with the ability to load up to 288 patient samples in a continuous, random-access workflow resulting in on-demand, high throughput testing. Additionally, the NeuMoDx Systems allow laboratories to efficiently validate their own SARS-Cov-2 Laboratory Developed Tests, including those provided by WHO and the CDC, in order to immediately improve throughput and increase the volume of testing.
- Abbott’s IDNOW test approval for its own mPOC no special training system just occurred and is welcome as well. The system benefits from its thousands of placements globally. (Media reports say 18,000 in the U.S. but Abbott has not said that directly in a press release or to us). It was previously Alere’s system, which Abbott acquired in 2017. Both it and Cepheid have international placements, which will help if and when there are large developing world case loads.
- Qiagen’s Syndromic Panel: Netherlands-based Qiagen announced on March 24 that it had begun shipping QIAstat-Dx SARS-CoV-2 test kits to the United States under a new FDA Policy allowing the kits to be made commercially available. Now, QIAGEN received U.S. FDA EUA for QIAstat-Dx test kit, first and only syndromic solution integrating detection of SARS-CoV-2 coronavirus. The test can differentiate novel coronavirus from 20 other serious respiratory infections. QIAGEN has placed more than 1,100 QIAstat-Dx instruments worldwide in hospitals, clinics and laboratories.
- Immunoassays: We are at the beginning of the launch of serological tests. Finding antibodies in the patient which signal disease is one of the oldest test technologies and still very present in the laboratory in 2020. Their advantage is they are cheap and easy to scale testing. But they are hard to develop and can be less accurate than molecular testing. Immunoassays take long to develop because require modeling of antibodies to detect for COVID-19. (Though that work is not wasted -there’s some evidence they can help vaccine manufacture too, a useful side benefit. ) Right now there is some secondary action with these tests, such as using them to decide if PCR testing is needed, or using them where no other option exists. Eventually, Kalorama expects immunoassays to be developed and to take over as routine tests. For a crisis, PCR seems logical. Major POC immunoassay players include Sekisui Diagnostics, Becton Dickinson, and Quidel.
- Ancillary/Secondary COVID-19 Tests: At least one immunoassay is seeing usage, though not for direct detection of the disease. Bio-Techne Corporation said their ProteinSimple™-branded Ella™ Automated Immunoassay platform is being used to detect Cytokine Release Syndrome (CRS) in real-time. Cytokine Release Syndrome represents a critical point in individuals with severe COVID-19 disease where immune molecules, called cytokines, attack the patient’s organs, representing a critical and potentially fatal point in disease management. The test results are available in a few hours and can be repeated throughout the course of care to help guide hospital care and to measure the response to experimental drugs given in clinical trials for COVID-19 patients. Another firm, BioMedomics, Inc., a small research and development firm in Research Triangle Park, created one of the world’s first rapid tests to assist in the detection of COVID-19, the disease caused by the novel coronavirus. The test only requires a small blood sample and can deliver results within 15 minutes. The company is encouraging its use as a first-line test, to decide if testing is necessary.
In previous reports analysts have warned that globalization comes with it disease and that the world will see more emerging diseases. This has come to fruition in recent weeks.
The Molecular Diagnostics Industry is Large and Capable
It’s worthwhile to consider that one of the first tasks of DNA-based when they arrived on the scene was the AIDS threat. The recent production of innovative assays by molecular diagnostics companies demonstrates the industries ability to respond to a new threat, as they had with HIV, Ebola, Zika, West Nile and others. The molecular diagnostics industry has large and well-financed companies such as Roche, Danaher, BD, Abbott, bioMerieux, Qiagen and Hologic. We noted last year that the molecular diagnostics market is larger than the economies of many countries. For instance, the market exceeds the individual GDPs of the Kyrgyz Republic at 8 billion or Fiji at $5 billion, or the smallest independent GDP in the world, the tiny 9-island nation of Tuvalu at $48 millions. More molecular diagnostic instruments and reagents will be sold this year than the GDP of Bermuda, Kosovo, and Sierra Leone, as well as those of 44 other nations,
There are a formidable amount of testing systems for SARS-CoV-2 at the current time. Enough to accomodate a wide swath of vendor placements at hospital labs and physician offices, clinics and pharmacies. The next phase will be staffing and being sure PPE and swabs are available for testing staff.
US FDA EUAs as of March 27:
- Becton, Dickinson & Company (BD) BioGX SARS-CoV-2 Reagents for BD MAX System
- Ipsum Diagnostics, LLC COV-19 IDx assay
- Cellex Inc. qSARS-CoV-2 IgG/IgM Rapid Test
- QIAGEN GmbH QIAstat-Dx Respiratory SARS-CoV-2 Panel
- NeuMoDx Molecular, Inc. NeuMoDx SARS-CoV-2 Assay
- Luminex Molecular Diagnostics, Inc. NxTAG CoV E
- Abbott Diagnostics Scarborough, Inc. ID NOW COVID-19
- BGI Genomics Co. Ltd Real-Time Fluorescent RT-PCR Kit for Detecting SARS-2019-nCoV
- Avellino Lab USA, Inc. AvellinoCoV2 test
- PerkinElmer, Inc. PerkinElmer New Coronavirus Nucleic Acid Detection Kit
- Mesa Biotech Inc. Accula SARS-Cov-2 Test
- BioFire Defense, LLC BioFire COVID-19 Test
- Cepheid Xpert Xpress SARS-CoV-2 test Healthcare Providers
- Primerdesign Ltd. Primerdesign Ltd COVID-19 genesig Real-Time PCR assay
- GenMark Diagnostics, Inc. ePlex SARS-CoV-2 Test
- DiaSorin Molecular LLC Simplexa COVID-19 Direct assay
- Abbott Molecular Abbott RealTime SARS-CoV-2 assay
- Quest Diagnostics Infectious Disease, Inc. Quest SARS-CoV-2 rRT-PCR
- Quidel Corporation Lyra SARS-CoV-2 Assay
- Laboratory Corporation of America (LabCorp) COVID-19 RT-PCR Test
- Hologic, Inc. Panther Fusion SARS-CoV-2
- Thermo Fisher Scientific, Inc. TaqPath COVID-19 Combo Kit
- Roche Molecular Systems, Inc. (RMS) cobas SARS-CoV-2
- CDC 2019-nCoV Real-Time RT-PCR Diagnostic Panel (CDC)
- New York SARS-CoV-2 Real-time Reverse Transcriptase (RT)-PCR Diagnostic Panel (Wadsworth Center, New York State Department of Health)
These approvals are a mix of tests that are complete instruments and tests that can be run on other systems, and lab-developed tests. The TaqPath COVID-19 Combo Kit can be run on a host of systems, not simply that of its manufacturer Thermo Fisher Scientific. It’s also useful to note that BD Max has CE marked tests for COVID now, which will see that product used in a lot of the cases in Italy, Spain and France.
Congress Passes CARES Act
The U.S. Senate has passed a $2.2 trillion spending bill — dubbed the CARES Act — designed to provide economic stimulus and fund the effort to combat the SARS-CoV-2/COVID-19 epidemic in the U.S. There will be a great deal of attention on small business loans and checks to American taxpayers, but the bill also contains provisions of interest to laboratories and IVD companies.
Among the provisions: Health plans cannot pass off costs to consumers outside of their normal premiums. Group health plan or health insurers must cover COVID-19 testing (Section 3717) without imposing cost sharing such as deductibles, co-payments, and coinsurance. Prior authorization requirements on COVID-19 diagnostics are banned during the emergency period. Unlike prior legislation, the CARES Act not only applies to tests that received 510(k) clearance but also includes tests being prepared for emergency use authorization from the FDA. Or those being prepared for state authorities.
South Korean Firm Blends AI and Portable X-Ray Testing to Power Up COVID-19 PCR
South Korean Firm JLK Inspection Inc. has added another dimension to RT-PCR testing for COVID-19 with AI and imaging enhanced diagnostic aids. The company’s product is its AI Total COVID-19 Care based on its AIHuB. AIHuB conducts analysis from MRI, CT, X-ray and mammography imagery with an AI-enabled technology that encompasses a wide variety of diagnostic techniques to pinpoint illnesses such as stroke, Alzheimer’s and cancer. This has been applied to COVID-19 in South Korea, where JLK has connected their system to an RT-PCR test. The company’s AI Total COVID-19 Care is comprised of three products, including AI Software that triages the pneumonia patients develop, a PCR test and a portable X-ray
Could Better IT Double U.S. COVID-19 Testing Capacity?
There are more labs with capacity to test for COVID-19, using Thermo Fisher TaqMan assays for instance, than are currently testing, according to lab IT (LIMS) company Ovation.io. With better information technology, could the COVID-19 testing capability of the United States be doubled? Scientific data management and clinical informatics firm Ovation.io wants its cloud-based laboratory information management system to serve as a hub for many of the estimated 2,500 molecular diagnostics labs in the US that do not currently offer COVID-19 testing. Ovation is offering out-of-the-box support for COVID-19 testing and reporting in the Ovation LIMS.
Ready to use capabilities include online order entry, standardized infectious disease workflow, automated interpretation following FDA and CDC guidelines, branded report template, and multimodal report delivery.
Test Equipment and Worker PPE Remain an issue
Testing cannot fully be brought to bear without proper protection for those operating the tests and collecting the samples. Supplies of PPE will be a challenge for laboratories and healthcare workers, and could limit test volume. Some supplies such as COVD-19 reagents or RNA sample extraction kits remain challenging for test makers, even where innovative instruments are daily appearing on the scene.
JAMA Network Calls for Creative ideas for Increasing PPE Supply
Orders for standard/disposable masks are on long back-orders, due to both demand and supply chain issues. Other hospitals across the country are reporting the same supply concerns. A recent JAMA Network article soliciting suggestions for PPE is at over 200 comments:
- Many suggestions advising using ultraviolet light towers to irradiate high numbers of masks, which were originally designed to only be used once.
- While fabric masks are not to be used in the care of COVID-19 patients, according to the CDC, fabric masks are a crisis response option when other supplies have been exhausted. Fabric masks can also be helpful in other areas of patient care as supplies of PPE are depleted. Deaconess Medical Center has a video dedicated to the making of masks: https://youtu.be/9tBg0Os5FWQ
- Many suggestions that dentists donate extra masks. One commenter estimated in Maryland alone, there are about 1000 surgical masks in stock (about 2 weeks worth). According to my research there are about 2,500 dental practices in Maryland. which would mean 2.5 million masks, of which a large portion may no longer be needed due to dentists cancelling elective appointments.
- A simple “Aerosol Box,” made of clear plastic which helps physicians perform endotracheal intubations, was created by Lai Hsien-yung , an anesthesiologist with Mennonite Christian Hospital in Hualien, Taiwan.
- Other suggestions including using plastic walls or even plastic curtains like those used in construction or renovation could be used to isolate part of patient rooms. These would allow for eyeballing and IV lines could go from the patient part of the room to outside.
- Using adapted snorkel masks as PPE were the suggestion of more than a few commenters, and they were completely serious. One suggested hospitals “Combine “full face” diving masks with 3D printing to adapt the snorkel area with a p100 filter, using 1 instead of the usual 2 filters. These have a good sealing and should be relatively low cost; the filter should be good enough for 1 month, and the mask should be easy to clean.”
SARS-CoV-2 Replication in Upper Respiratory Track Seen as Culprit
Why is this infectious disease threat more daily than influenza, Ebola, Zika or West Nile? The newness of the infection strain and the means of viral replication may be one of many culprits. Per the New England Journal of Medicine: “The efficiency of transmission for any respiratory virus has important implications for containment and mitigation strategies. The current study indicates an estimated basic reproduction number (R0) of 2.2, which means that, on average, each infected person spreads the infection to an additional two persons. “
This seems to be due to the heavy and actively replicating presence of virus in the upper respiratory track. More: “Recent reports of high titers of virus in the oropharynx early in the course of disease arouse concern about increased infectivity during the period of minimal symptoms.”
Patients May Continue to Shed Virus After Symptom Clearance
Patients may continue to shed the virus that causes COVID-19 according to a study published online March 23 in the American Thoracic Society’s (ATS) American Journal of Respiratory and Critical Care Medicine. Researchers found that patients treated for mild COVID-19 still had the virus for up to eight days after symptoms resolved — a result that underscores the difficulty of curbing the disease. Their study provides “initial insights” into the ability of the virus to persist even after the resolution of [symptoms] for as long as eight days, which may pose a significant challenge in controlling the spread of the disease. The COVID-19 pandemic is the “third and the most lethal outbreak of coronavirus in the 21st century,” the artcile noted, and its ability to spread appears to arise from transmission from asymptomatic patients. “Cases have been reported where a patient could infect their close contacts even after ‘apparent recovery’ from the infection,” the authors wrote. “This warrants [investigation into] the ‘shedding window’ after the clinical recovery of the patient.” The study sought to investigate the time frame of “viral clearance” as it related to the resolution of COVID-19 symptoms. Their study included 16 patients (median age, 35 years) who were treated for the disease and released from the hospital between January 28 and February 9. The time from infection to the onset of symptoms was five days for all patients except one, and the average duration of symptoms was eight days.
Viral Load/ Symptom Connection: Conflicting Studies
The issue of COVID-19 viral load and severity of illness. has been looked at but not sufficiently answered https://www.newscientist.com/article/2238819-does-a-high-viral-load-or-infectious-dose-make-covid-19-worse/ For instance, health workers investigating the covid-19 outbreak in the Lombardy region of Italy looked at more than 5,000 infected people and found no difference in viral load between those with symptoms and those without. They reached this conclusion after tracing people who had been in contact with someone known to be infected with the coronavirus and testing them to see if they were also infected. Similarly, when doctors at the Guangzhou Eighth People’s Hospital in China took repeated throat swabs from 94 covid-19 patients, starting on the day they became ill and finishing when they cleared the virus, they found no obvious difference in viral load between milder cases and those who developed more severe symptoms. Although it is difficult to draw firm conclusions at this stage, such studies “may impact our assumptions about whether a high number of viral particles predisposes to a more serious disease”, says van Schaik. For influenza, a higher infectious dose has been associated with worse symptoms. It has been tested by exposing volunteers to escalating doses of influenza virus in a controlled setting and carefully monitoring them over several weeks. This hasn’t been done with covid-19, and is unlikely to happen, given its severity.
Full Weight of mPOC Yet to Be Brought to Bear
In point of care PCR there are approvals, but with caveats that it will take time to deliver systems. There are now molecular point-of-care approvals with BioFire and Cepheid and Abbott. But it’s still the logical answer. Molecular Point of Care (mPOC), which analyze DNA or RNA, typically using polymerase chain reaction (PCR) technology or another form of nucleic acid amplification, make all the sense in the world where you have to know quickly if a patient has COVID-19, where there are carriers without symptoms, and where patients should be isolated. They make even more sense where there is a potential non-patient population that may wish to know if they’ve been exposed.
Credo Diagnostics Biomedical: VitaPCR platform, COVID-19 assay received a CE Mark. Oxford Nanopore Technologies is another player, having announced in January that it had shipped hundreds of its MinION units, which are portable devices for real-time DNA and RNA sequencing, and related consumables to China, the center of the novel coronavirus outbreak. Ubiquitome is planning to develop a coronavirus test on its Liberty16, a mobile, real-time PCR system with two to three hours of battery life.
Other companies that are developing or have developed mPOC tests for SARS-CoV-2/COVID-19 include the following:
- Diagnostics for the Real World: SAMBA II COVID-19 test
- HiberGene Diagnostics: HG Swift (can use battery power), COVID-19 assay based on loop-mediated isothermal amplification (LAMP)
- Molbio Diagnostics: Truelab, Truenat SARS-CoV-2, Trueprep, and Truenat instruments
- Mobidiag: Novodiag COVID-19 + influenza A/B, multiplex test
- Qiagen: QIAstat-Dx Respiratory 2019-nCoV test
- QuantuMDx: Q-POC, handheld
The number of labs in the U.S. that are qualified for CLIA high-complexity testing is on the order of 10,000 to 11,000. Based on experience with influenza, which is similar in some respects, the number of tests that are needed for coronavirus will likely rise to tens or even hundreds of thousands per week.
The overlap of symptoms with flu could create a need to rapidly scale up testing to differentiate these cases from coronavirus. Some companies such as Cepheid and Mobidiag are developing multiplex panels for flu and coronavirus to better distinguish the diseases.
Will We See Fundamental Change in IVD?
This is a worthwhile question. It’s possible diagnostics will not be the same after this crisis in so many ways, though Kalorama can only comment on the IVD market landscape and to a limited degree the vaccine landscape. It’s useful to point out as a counter to any notion of massive change in the future that the healthcare systems of the world have seen many diseases temporarily get attention, only to lose that attention when the immediate problem is cured, or when there is some other large-scale threat.
That being said, we’d expect some deep thinking about the pace of test approval in the coming months. The contrast of effective [though still to be measured] Chinese and Korean testing, and other CE Marked test employed in Europe versus the slow rollout of testing in the United States will be an unavoidable one in policy discussions. This added to the CDC’s snafu in kit delivery , its insistence on commercialization and in waiting on approval of LDTs, would make a powerful argument for reform.
This from the New England Journal.
“This crisis is a stark reminder of the ongoing challenge of emerging and reemerging infectious pathogens and the need for constant surveillance, prompt diagnosis, and robust research to understand the basic biology of new organisms and our susceptibilities to them, as well as to develop effective countermeasures.”
On the spending side, there is already spending for stockpiling and test development in the CARES act and we’d expect that to continue and some continued thought given to building diagnostics innovation long-term. It’s reasonable to predict that IVDs move from their current status as rationed costs to getting closer to reaching the “first-line” status in healthcare they’ve been seeking.
It would be presumptive to estimate market effects until the true amount of testing revenues by major firms are seen. Significant costs were likely expended in R&D at major firms during the crisis, and resources devoted to test development.
As a very basic measure – it’s not unusual for Kalorama or other analysts to find flu testing companies grow 10% to 20% during a particularly menacing flu season. This provides a floor for the type of revenue increase companies will have during this to-be-completed quarter, but not a ceiling.
Testing for COVD-19 in the United States: What Happened? What’s Happening Now?
Testing was a recognized failure in the crisis. In the coming investigations after the crisis has subsided, many will blame inadequate Federal coordination, the insistence on centralized testing at CDC that did not match the scope of the virus’s spread, and certainly the manufacture of faulty test kits at the CDC. [The CDC’s test, we should say worked, but an extra control added did not.] In our perspective, it has long been the case that IVDs have been relegated to a second thought in a treatment-focused healthcare system, and worse, a cost to be reduced wherever possible.
To quote a Harvard Business Review article “Why is the US Behind on Coronavirus Testing?” https://hbr.org/2020/03/why-is-the-u-s-behind-on-coronavirus-testing
“Testing is also needed to address the uncertainty in making decisions about patient treatment, resource allocation, policy, and so much more. Answers to questions such as ‘When should we relax social distancing measures — and for whom?’ or ‘How many ventilators are needed in hospitals?’
While South Korea had tested about 4,000 people per million of its population at the time, the United States had just run five tests per million — despite the fact that they both reported their first cases at essentially the same time (on January 21 and 20).
The discrepancy was surprising because the genome of the virus had been available since January and scientists had figured out the diagnostics shortly thereafter, using proven molecular methods first discovered in the 1970s.”
Feb 29th FDA Policy
In light of testing failures – On Feb 29th, FDA announced a new policy is for certain laboratories that develop and begin to use validated COVID-19 diagnostics before the FDA has completed review of their EUA requests. They opened up validated testing to high complexity labs that could perform it. The FDA said can issue an EUA to permit the use, based on scientific data, of certain medical products that may be effective in diagnosing, treating or preventing a disease or condition when there is a determination, by the Secretary of Health and Human Services (HHS), that there is a public health emergency or a significant potential for a public health emergency that has a significant potential to affect national security or the health and security of U.S. citizens, and a declaration that circumstances exist justifying the medical products’ emergency use. At that time, the FDA was still sounding a concern about accuracy of tests, Director Hahn saying “We will continue to help to ensure sound science prior to clinical testing and follow-up with the critical independent review from the FDA”
Significance of March 16th Guidance
On March 16th, the policy loosened further. In a move it called an “unprecedented policy,” the U.S. Food and Drug Administration (FDA) on March 16 once again relaxed its regulations on diagnostics to be used to test for the novel coronavirus. The new rules allow states to regulate diagnostics and let vendors sell tests before getting emergency approval.
The FDA has been under heavy pressure to ease its regulations on diagnostics to get more tests into the field for the SARS-CoV-2 coronavirus, which causes the COVID-19 respiratory disease. Clinicians and public health authorities have claimed that not enough tests are available to meet demand, so the agency has made a series of regulatory changes over the last several weeks that relax its oversight.
The March 16 policy could be the biggest revision yet. One change includes a move that lets states that wish to do so take over regulatory oversight of diagnostic tests that up to now have been regulated by the FDA. The FDA said the change extends to other states the authority the FDA gave last week to the New York State Department of Public Health to approve diagnostic tests within the state.
The second part of the new guidance lets commercial test developers sell their products on the market without the need for an emergency use authorization (EUA). Under the February 29 guidance, the FDA granted EUA waivers to labs that are certified to perform high-complexity testing, but commercial vendors were not covered by that policy.
In a third change, the FDA provided guidance to developers of serological tests, which test the blood for signs of coronavirus infection. The agency said that while serological tests are less complex than molecular tests and only identify antibodies, it does not intend to object to vendors developing these tests for SARS-CoV-2 infection.
When it comes to changes to EUA rules, the FDA said that diagnostic tests developed by commercial manufacturers can be used in patients before getting emergency authorization. The FDA is requiring that it be notified within 15 business days that such use is occurring, and that labs and vendors be transparent in how they validate the tests. The FDA will then review this data. The changes upend the traditional regulatory pathway by which the FDA reviews medical devices and diagnostics. But the agency said it has changed its approach based on the evolving nature of the coronavirus pandemic and in an effort to make more tests available.
The FDA approved commercial systems in mid-March. The first commercial kits were introduced in January by Roche in collaboration with partners such as TIB Molbiol Berlin. These products included the Wuhan RdRp assay, which is specific for detecting SARS-CoV-2, and the Wuhan N-gene3 test, which tests for SARS-CoV-2 plus other related types of coronaviruses. These reverse transcription polymerase chain reaction (RT-PCR) tests were developed for use on Roche’s LightCycler 480 and MagNA Pure 24 instruments and were widely used in China. In mid-March, Roche received an EUA in the U.S. and began shipping new COVID-19 tests for use on its cobas 6800/8800 systems, which provide about a tenfold higher throughput.
These larger systems contain liquid handling modules that are fully automated, incorporating the RNA extraction and sample preparation steps followed by amplification and detection. This allows them to run a 96-well plate of samples in about four hours. The automation enables 384 test results or 960 test results in eight hours for the 6800 or 8800 systems, respectively.
Also in mid-March, Thermo Fisher Scientific became the second company to receive an EUA for a commercial product — for its TaqPath COVID-19 combo kit, which consists of the TaqPath COVID-19 RT-PCR kit and the TaqPath COVID-19 control kit for simplified ordering. The product can be used to evaluate up to 94 patient samples in under four hours.
The test is designed for use with the Applied Biosystems 7500 Fast Dx real-time PCR system and the associated Applied Biosystems COVID-19 Interpretive Software, but according to the FDA it can also be run on other authorized instruments.
As of March 24, the FDA had approved a total of 15 tests via the emergency use authorization pathway (see box). The agency has said that more than 80 diagnostic test developers have sought its help in developing and validating tests through the EUA process.
Cepheid was among the companies that were likely candidates for an early EUA for coronavirus testing, based on its track record in testing for other infectious diseases and Kalorama Information market research. As small-footprint, near-patient systems, molecular POC (mPOC) products are well-placed to play an important role during the pandemic. Other near-patient systems have been developed by Singapore-based Credo Diagnostics Biomedical, which has received a CE Mark for its test, and GenMark Diagnostics, whose partially automated ePlex SARS-CoV-2 test received an EUA last week.
But Cepheid’s new test is a significant development for the following reasons:
Cepheid’s product has a greater installed base than other systems and a design that fosters easier use in a clinical setting.
The speed of 45 minutes is much faster than any approved test Kalorama has read of so far — several magnitudes faster than the speed of the tests recently approved.
No specialty operator training is required to administer the test and determine a result. This means it can be used in a doctor’s office or retail clinic; 45 minutes is a brief enough time to await results at the point of care under normal circumstances.
Extraction steps using a kit are not necessary; this is handled in the machine. There are currently backlogs with such kits at major manufacturers.
Kalorama’s market research has predicted that mPOC tests will lead the fight in meeting the demand for COVID-19 testing with accurate and fast results. Lab staff is at a premium, hospitals are taxed, and testing needs to happen where it can be useful to isolate patients. Our latest report on the market was released March 4.
BARDA funding for POC, panels and automated tests
POC diagnostics have benefited from the support of government programs. In February, the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA) launched the Easy Broad Agency Announcement (EZ-BAA), a solicitation for funding specifically for diagnostics for the new coronavirus, with up to $749,000 available for each project. The agency has stated that POC testing is a significant priority.
Qiagen, which is in the process of being acquired by Thermo, benefited from BARDA funding. The company recently began shipping its QIAstat-Dx respiratory SARS-CoV-2 panel in the U.S.
The mPOC tests for SARS-CoV-2 are currently in various stages of development or availability, but it appears that most will take a few weeks or months to be made widely available. These platforms are designed to be CLIA-waived but are often ultimately approved for mostly moderate-complexity tests. Many are first made available as research-use-only (RUO) products, which can, in fact, be used as LDTs if regulations and proper validation processes are followed.
Where did SARS-CoV-2 come from?
Coronaviruses are a large family of viruses that can cause illnesses that range widely in severity. On December 31, 2019, the Chinese authorities alerted the World Health Organization of an outbreak of a novel strain of coronavirus causing severe illness, which was subsequently named SARS-CoV-2.
Shortly after the epidemic began, Chinese scientists sequenced the genome of SARS-CoV-2 and made the data available to researchers worldwide. The Nature Medicine article explains some of what they have discovered.
Unique molecular backbone
The genomic comparison of the receptor-binding domain (RBD) in the spike protein of SARS-CoV-2 against other closely related betacoronaviruses and the original SARS-CoV virus revealed that SARS-CoV-2 has significantly higher binding affinity with human angiotensin-converting enzyme 2 (ACE2) than any of the other viruses. The RBD of SARS-CoV-2 is optimized for binding human ACE2 with an efficient solution that is different from other SARS-CoV-like coronaviruses. The sequences are so different, in fact, that the scientists involved in the project concluded that they are a result of natural selection and not based on a template for genetic modification.
Analysis of the SARS-CoV-2 spike protein showed the addition of O-linked glycans, created by an inserted proline to the sequence, that flank a polybasic cleavage site in the spike are believed to be responsible for the virus’s high level of infectivity and host range. Polybasic cleavage sites have not been observed in other lineage B betacoronaviruses, although other human betacoronaviruses do have those sites. The major changes to the molecular backbone of SARS-CoV-2 compared with other coronaviruses provide evidence that the changes occurred by natural selection. If someone were seeking to engineer a new coronavirus as a pathogen, they would have constructed it from the backbone of a virus known to cause illness. But the scientists found that the SARS-CoV-2 backbone differed substantially from those of already known pathogenic coronaviruses.
There are two likely scenarios for SARS-CoV-2 origin, according to the scientists involved in this analysis. First, based on the similarity of bat SARS-CoV to SARS-CoV-2, it is likely that bats served as an animal reservoir in which natural selection occurred before jumping to humans.
No cases of direct bat-human transmission have been documented, however, suggesting that an intermediate host was likely involved between bats and humans. The spike RBD in bat SARS-CoV diverges from SARS-CoV-2, suggesting that it may not bind efficiently to human ACE2. Alternatively, some coronaviruses from pangolins — armadillo-like mammals found in Asia and Africa — have an RBD structure very similar to that of SARS-CoV-2.
Neither bat betacoronaviruses nor the pangolin betacoronaviruses sampled thus far have polybasic cleavage sites. While no animal betacoronavirus has been identified that is sufficiently similar to have served as the direct ancestor of SARS-CoV-2, the diversity of coronaviruses in bats and other species is massively undersampled.
The mutations observed in SARS-CoV-2 can arise by natural selection, so acquisition of both mutations in the polybasic cleavage site and the spike protein would be possible in high-density populations and with an ACE2 encoding gene that is similar to the human ortholog.
In this case, the current epidemic would probably have emerged rapidly as soon as humans were infected, as the virus would have already evolved the features that make it pathogenic and able to spread between people.
In the second scenario, a nonpathogenic version of the virus jumped from an animal host to humans, from which it acquired pathogenic genomic features through adaptation during undetected human-to-human transmission. As of March 17, all SARS-CoV-2 genomes sequenced from the COVID-19 coronavirus outbreak have a common ancestor. The presence of a very similar RBD in pangolins infers that they may be the animal host from which the virus jumped to humans. In this case, the insertion of the polybasic cleavage site must have occurred during human-to-human transmission.
Estimates of the timing of the most recent common ancestor of SARS-CoV-2 point to late November 2019 to early December 2019 and the earliest confirmed cases in January 2020. This timetable indicates that there could have been a presumed period of unrecognized transmissions in humans between the initial zoonotic event and the acquisition of the polybasic cleavage site.
It is difficult, if not impossible, to know at this point which of the scenarios is most likely, cautioned study co-author Andrew Rambaut, PhD, from the University of Edinburgh. If the SARS-CoV-2 entered humans in its current pathogenic form from an animal source, it raises the probability of future outbreaks, as the illness-causing strain of the virus could still be circulating in the animal population and might once again jump to humans. The chances are lower of a nonpathogenic coronavirus entering the human population and then evolving properties similar to SARS-CoV-2.
As the U.S. struggles to cope with skyrocketing demand for COVID-19 diagnostic tests, it is turning for help to South Korea, a country that has become a model for how to deal with the novel coronavirus outbreak, according to published reports. https://www.labpulse.com/index.aspx?sec=sup&sub=mic&pag=dis&ItemID=800965The novel coronavirus is presenting the global community with challenges in identification and classification. Due to the sneaky spread of the disease and delayed emergency responses, the ability to test for the disease is inadequate to stay ahead of its progress.
Viral outbreaks are not new in the 21st century, noted Ralph Baric, PhD, an epidemiology professor at the University of North Carolina at Chapel Hill. Baric provided an update on the state of the coronavirus, including how the current outbreak began and what’s being done to combat the spread of the disease, at a briefing held on February 26 by the Congressional Biomedical Research Caucus.
Why it’s difficult to stay ahead of SARS-CoV-2
Researchers have identified several molecular drivers that provide an advantage to SARS-CoV-2. First, all coronaviruses can traffic easily between species. They have the ability to fix errors in their genomes during replication and can tolerate high levels of mutations, making it easy for them to adapt to changes. Second, SARS-CoV-2 was primed to cause disease. It can bind to receptors in both animals and humans and causes the deadly acute respiratory distress syndrome (ARDS). Lastly, SARS-CoV-2 can spread asymptomatically. This makes it nearly impossible to track the spread of the virus and, therefore, it is difficult to contain.
The importance of confirming cases
Due to the particularly dangerous nature of asymptomatic spread, epidemiological models predict that SARS-CoV-2 will inevitably spread in the U.S. This underlies the importance of diagnostic testing and having rapid methods to detect the virus, even in patients who show no symptoms. Despite the first case of coronavirus being reported on December 1, 2019, Chinese scientists did not share genomic sequences until January 9-11. It was only then that other countries could begin emergency efforts in earnest.
In Baric’s view, the Chinese made three classic mistakes at the onset of the outbreak due to their “SARS phobia.” They initially stated that the virus was not SARS-related but rather a novel coronavirus. Additionally, initial reports specified that the virus was not pathogenic with no evidence of human-to-human transmission. This may be why national and international entities had a delayed response to the danger of the emerging virus.
The need for diagnostic testing kits in the U.S. is urgent. Concurrent with flu season, the tendency for sick individuals is to believe they have the flu. Without diagnostic kits, we will never know if these patients actually have the coronavirus, Baric said. Due presumably in part to the limited availability of testing kits, as of February 28, only 15 confirmed cases of COVID-19 had been reported in the U.S. (excluding people who returned to the U.S. on State Department chartered flights).
The U.S. Centers for Disease Control and Prevention (CDC) began issuing 2019-nCoV real-time reverse transcription polymerase chain reaction (RT-PCR) diagnostic panels to qualified labs on February 4. Many of these kits had to be recalled due to inaccurate primers. The agency this week developed and published a new protocol that it said will allow many U.S. labs to conduct testing using existing kits.
Countermeasures in development
Currently, two types of therapies are being developed to combat SARS-CoV-2: antiviral drugs and vaccines. Vaccines are difficult to develop because they are not efficacious in aged patients who are most at risk for COVID-19 and due to the potential for immune pathology caused by vaccination (Th2 response).
Vaccines will be crucial to eliminating the new coronavirus, Baric said, which is why his team is working on developing vaccines that protect not only against known strains of coronaviruses but also viruses that may occur in the future.
Meanwhile, drug repurposing efforts have led researchers to use broad-spectrum antiviral drugs as potential therapies. These small molecules can be used under compassionate care laws, meaning they can rapidly enter the clinic (within one month).
Gilead Science’s remdesivir, a broad-spectrum antiviral drug initially developed for the treatment of Ebola, is set to be studied in two phase III studies for the treatment of adults with COVID-19. Gilead is interested in increasing the bioavailability of the product so it can be administered as a tablet instead of intravenous therapy. The studies are set to start enrolling in March, according to the company.
The Congressional Biomedical Research Caucus was established in 1989 to broaden the support and knowledge of basic and clinical biomedical research issues throughout the U.S. Congress in a bipartisan manner. The caucus membership is comprised of 75 members of the House of Representatives and eight members of the Senate with Reps. Steve Stivers (R-OH), Jackie Speier (D-CA), Steve Cohen (D-TN), and John Curtis (R-UT) serving as co-chairs.
The Coalition for the Life Sciences (CLS) is an alliance of professional organizations working together to foster public policies that advance basic biological research and its applications in medicine and other fields. The issues addressed by the CLS include science education, professional training, and the funding, management, and oversight of scientific work, especially by the federal government.